Ionis Pharmaceuticals, Inc. (IONS) Earnings Call Transcript & Summary

Good afternoon, and welcome to Ionis' conference call to review the Phase III data for eplontersen. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. Please begin.

Thank you, Jason. Hello, and thank you for joining us as we discuss the results from our Phase III NEURO-TTRansform study of eplontersen in patients with hereditary ATTR polyneuropathy, which were presented yesterday at the American Academy of Neurology Annual Meeting. Before we begin, I encourage everyone to go to the Investors section of the Ionis website to view the press release we issued yesterday as well as the AAN presentation and poster and the slides we will be using on today's webcast. I would first like to draw your attention to Slide 2, which contains our forward-looking statements. Our discussion today will contain forward-looking statements based on our current expectations and beliefs. Such 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. I would also like to remind you that eplontersen is an investigational medicine that is currently under regulatory review in the U.S. Today, Brett Monia, our Chief Executive Officer, will provide an introduction. Eugene Schneider, Chief Clinical Development Officer, will provide an overview of our eplontersen development program, Dr. Sam Tsimikas, our Senior Vice President of Global Cardiovascular Development and the eplontersen development leader for ATTR cardiomyopathy will discuss the second indication we are pursuing with eplontersen, ATTR cardiomyopathy and our ongoing cardiotransform study. Onaiza Cadoret, Chief Global Product Strategy and Operations Officer, will provide an update on our pre-commercial preparations. And we are very pleased to have with us today Dr. Sami Khella Chief of the Department of Neurology at Penn Presbyterian Medical Center and Professor of Clinical Neurology University of Pennsylvania School of Medicine. Dr. Khella is a world expert in neurology and one of the principal investigators on the eplontersen program. He also presented the data from the neuro transform study at AAN yesterday. So we're happy to have him with us to discuss the eplontersen results and to be on our on hand to answer your questions. With that, I'll turn the call over to Brett.

Thanks, Wade, and thank you, everyone, for joining us on today's webcast. We are very pleased with the positive results from the week 35 interim analysis and week 66 final analysis from the eplontersen NEURO-TTRansform study in patients with ATTR polyneuropathy. We're equally pleased to be joined by one of the key experts in the field of ATTR and with those is , Dr. Sami Khella. Sami presented these data yesterday at AAN and is here today to walk us through these results again and to provide his perspective on the significance of the data for patients with hereditary ATTR polyneuropathy. There are an estimated 40,000 addressable patients with ATTR polyneuropathy worldwide. However, less than 20% of those patients are currently receiving approved treatments. We are very pleased to report that in the Phase III NEURO-TTRansform study, eplontersen halted neuropathy progression and improved the quality of life of ATTR polyneuropathy patients through 66 weeks. Based on these data, we are confident in eplontersen's strong product profile and its potential to be an important new treatment for patients who remain underserved. There were a number of key takeaways from yesterday's presentation, a few of which I'll highlight here before Eugene and Dr. Khella dive deeper into the results. Eplontersen met all co-primary endpoints with a high degree of statistical significance, including demonstrating robust and consistent reductions in serum TTR. Significant improvements in measures of neuropathy and improvements in quality of life compared to placebo with a substantial number of patients demonstrating improvement compared to baseline values at both week 35 and week 66. All of this with a favorable safety and tolerability profile through 66 weeks of treatment. Eplontersen also achieved statistically significant and clinically meaningful benefit across all 4 secondary end points, further reinforcing eplontersen strong product profile. These results also further strengthen our confidence in eplontersen's potential in the broader ATTR cardiomyopathy indication that we are evaluating in our ongoing cardiotransform study. Based on these strong data, together with at-home self-administration with an auto-injector, we believe if approved that eplontersen will be an important treatment for this largely untapped patient population. We and our partner, AstraZeneca, look forward to bringing eplontersen to patients around the world, beginning first in the United States with the potential approval of our NDA in December. Before I turn the call over to Eugene, I'd like to thank the patients, families and clinicians who have participated in the neuro transform study and contributed to the positive results we are reporting this week. And with that, I'll pass the call over to Eugene, who will provide an overview of our eplontersen development program.

Thank you, Brett, I would also like to express my gratitude the gratitude to those in the ATTR community. This participation in our eplontersen development program enables us to share these important results with you today. We have a robust development program for eplontersen, our most advanced LICA drug designed to degrade hepatic TTR mRNA and inhibit the production of TTR protein, the root cause of TTR amyloidosis, also known as ATTR. We're developing eplontersen for two indications, for hereditary ATTR polyneuropathy and ATTR cardiomyopathy. In a few moments, Sami will discuss our ATTR cardiomyopathy development program and its current status. But first, let me remind you of the design and objectives of NEURO-TTRansform. The Phase III neuro transform study is a global, randomized, open-label study that enrolled 168 adult patients with Stage I or Stage II ATTR polyneuropathy. Patients were randomized in a 6:1 ratio to either 45 milligrams of eplontersen administered once monthly or 300 milligrams of inotersen administered once weekly. And as designed inotersen patients crossed over to eplontersen after 35 weeks. The Placebo arm from the Phase III inotersen neuro TTR study was used as an external control for the week 35 interim analysis and week 66 final analysis. Additionally, there will be an end of treatment analysis at week 85 and once patients reach week 85, they have an option to transition to an open-label extension study. This open-label extension study, or OLE, will continue to assess long-term efficacy, safety and tolerability of our [ ventures ] . At the week 35 interim analysis, the study has two co-primary end points, TTR reduction and the change in modified neuropathy impairment scale, or mNIS+7 composite scale. And at week 66, we included an additional co-primary end point the Norfolk Quality of Life diabetic neuropathy [ questionnaire ], which was a key secondary endpoint of week 35 analysis. TTR concentrations were measured immediately prior to the subsequent eplontersen dose by enduring trough, which means that the TTR reductions likely represent the most conservative estimates. The validated mNIS+7 scale was designed specifically to measure neuropathy impairment in patients with ATTR polyneuropathy in a clinical trial setting, the total score is the sum of six components or lower scores indicate less impairment and higher scores more impairment. The Norfolk Quality of Life Diabetic Neuropathy questionnaire is a validated instrument to measure quality of life in polyneuropathy patients. It assesses the severity of symptoms characteristic of ATTR polyneuropathy including pain, numbness and diarrhea and how these symptoms impact patients' ability to perform activities of daily living such as walking, dressing and feeding. These measures translate easily to the real world and are commonly used by clinicians to assess how treatment is benefiting their patients. I would now like to turn the call over to Dr. Khella for a discussion of the current ATTR treatment landscape and a closer look at the results from the 35 and 66-week analysis from NEURO-TTRansform.

Thank you, Eugene. TTR amyloidosis, or ATTR, is a systemic, and it's a rapidly progressive debilitating inherited disorder. It's inherited guestas an autosomal-dominant fashion, and it's ultimately a fatal disorder. It's characterized by many systems being affected. There are patients who have a cardiomyopathy, some patients have a peripheral neuropathy. Some patients have an overlap of the two. The disease can also affect the autonomic nerve system leading to early erectile function, severe orthostatic hypotension, diarrhea, cachexia, and weight loss. I've had patients in my practice, referred to me who has taken many years, actually, before they're diagnosed, so the delay in diagnosis becomes a problem in treating these patients because they don't do as well. The neuropathy in particular, will progress to a paralyzing illness they can't use their hands, they can't use -- they can't walk very well, have activities, problems with activities of daily living. So it can be quite a [Technical Difficulty]

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So as I said, this is a progressive and fatal illness. And as Eugene reviewed the neuro transform was designed to assess efficacy of eplontersen in measures of neuropathy and neuropathy specific quality of life parameters, in a broad spectrum of patients. The clinical characteristics seen in neuro transform were also consistent with patients that I see in my practice that I just described to you. Baseline demographics were generally well balanced between eplontersen-treated patients and the historical placebo control arm. There were a few minor differences driven by slightly younger and less severe population in neuro transform consistent with what we're seeing in the current treatment landscape. Additionally, there were slightly more eplontersen treated patients with V30M mutation and slightly more who were previously treated with a stabilizer. Propensity score weights were used to adjust for the minor differences between the two study populations in the week 35 and the week 66 efficacy analysis. The study had a high completion rate with 94% of patients in the eplontersen-treated group completing treatment compared to 83% of patients in the placebo group. The high completion rate speaks to both the high quality of the study and the favorable tolerability profile of eplontersen. Now on to the results. at week 35 and week 66, eplontersen achieved all co-primary endpoints. Eplontersen treatment resulted in a significant and sustained reduction in serum TTR concentration from baseline through week 66, and this persisted into week 66. Reduction in TTR was consistent over the treatment period and across treated patients as indicated by the small standard error bars. At week 66, eplontersen demonstrated an LS mean reduction in Serum TTR concentration of 82%, which was also highly statistically significant. And as Eugene mentioned, based on the timing of sample collection, these are the most conservative measures of TTR reduction. Now looking at the neuropathy measure, the mNIS+7 patients who received eplontersen showed a highly statistically significant and clinically meaningful difference in the LS mean change relative to external placebo at week 35 and week 66. The LS mean difference between eplontersen and placebo-treated patients was negative 9 points at week 35 and negative 25 points at week 66. Over time, the placebo groups mean mNIS +7 got progressively worse as their disease progressed. In contrast, eplontersen-treated patients the LS mean mNIS+7 score remained essentially flat over the course of the study, indicating a halting of progression of the neuropathy. Importantly, 53% of patients who completed eplontersen treatment showed improvement in neuropathy at week 66 compared to their baseline values. Now moving to the Norfolk Quality of Life score. Here again, eplontersen-treated patients show that highly statistically significant and clinically meaningful difference in the quality of life compared to placebo at week 35, which further improved through week 66. The LS mean difference between eplontersen and placebo-treated patients was negative 12 points at week 35 and negative 20 points at week 66. And as with mNIS+7, a majority of the eplontersen-treated patients also showed improvements in their quality of life compared to their base values. At week 66, Norfolk scores improved from baseline and 65% of patients who completed the eplontersen arm. Additionally, when looking at eplontersen's treatment effect on mNIS+7 and Norfolk scores, the significant improvements were consistent across all subgroups, including disease stage, mutation type and whether or not patients receive stabilizer treatment prior to entering the study. And a consistent treatment effect was also observed across mNIS+7 individual components and the Norfolk Quality of Life domains. Eplontersen also achieved statistically significant and clinically meaningful benefits across all four secondary endpoints at week 66 when compared to placebo. The secondary endpoint measures the frequency and the severity of some of the most debilitating physical symptoms and the reduced nutritional status that I discussed before that ATTR polyneuropathy patients experience providing an even greater picture of the benefits that eplontersen had on the patient's quality of life. For example, I was particularly pleased to see significant benefit in the modified BMI compared to placebo. MBMI Is a validated measure that clinicians often use to assess reduced nutritional status and cachexia, which means severe wasting, that is characteristic of ATTR polyneuropathy. Cachexia is often the ultimate cause of death in patients with this disease. Treatment with eplontersen prevented the dramatic reduction in modified BMI that was observed in the placebo-treated patients. I was also pleased to see a stabilization in measures of overall physical health in the SF-36, which further reinforces the findings in the Norfolk Quality of Life primary endpoint providing an even broader view into patients' perceptions of their general health and ability to partake in activities of daily living. So as you can see, the consistency of the positive week 35 and week 66 data across all elements of disease measurements demonstrates how eplontersen can significantly improve outcomes in patients with ATTR polyneuropathy. Now turning to the safety. The overall safety and tolerability profile of eplontersen was favorable compared to placebo at week 66. Eplontersen and placebo groups had comparable rates of adverse events including those related to study drug and those that resulted in treatment discontinuation. No adverse events of special interest led to study discontinuation. This includes ocular AEs potentially related to vitamin A deficiency, thrombocytopenia or Glomerulonephritis. There were also no serious treatment emergent adverse events considered related to study drug in the eplontersen group. As previously reported, there were two deaths in the eplontersen group that were not considered related to study drug by the PIs, the investigators. Both deaths occurred before week 35 and were attributed to known complications of ATTR. Now to summarize the findings from neuro transform, eplontersen demonstrated a consistent and sustained benefit across all primary and secondary end points, the consistency in efficacy data is compelling and when compared with the favorable safety and tolerability profile, I believe that eplontersen is positioned to potentially become a very important treatment for patients with ATTR polyneuropathy. Now I'll turn it over to Sam.

Thank you, Dr. Khella. The positive efficacy and safety results we've seen in the NEURO-TTRansform study gives us even greater confidence for the performance of eplontersen in our ongoing CARDIO-TTRansform study in patients with ATTR cardiomyopathy. ATTR cardiomyopathy is caused by the accumulation of misfolded TTR protein in the cardiac muscle. Patients experience ongoing debilitating heart damage leading to progressive heart failure which results in death within 3 to 5 years from disease onset. ATTR cardiomyopathy includes both the genetics and the wild-type forms of the disease and is estimated to affect between 300,000 to 500,000 people around the world. People with hereditary ATTR often have a mixed phenotype in which they suffer from polyneuropathy due to the accumulation of TTR buildup in their nerves and cardiomyopathy due to the accumulation of TTR in their heart. The substantial reduction in TTR that we've now observed with eplontersen gives us further conviction in the potential for eplontersen to provide benefit for patients experiencing cardiomyopathy by reducing TTR accumulation in the heart. Additionally, the favorable safety and tolerability profile we have seen in ATTR polyneuropathy patients in the neuro transform study bodes well for patients with cardiomyopathy. We are conducting the most comprehensive study in patients with ATTR cardiomyopathy to date, positioning us to deliver a rich data set for this broad patient population. As a reminder, CARDIO-TTRansform is expected to enroll approximately 1,400 patients. The primary efficacy endpoint is a composite of cardiac, cardiovascular death and recurrent cardiovascular events. The study is designed to have a maximum 140-week treatment duration, and the protocol has an option for an earlier readout, which is based on criteria defined and detailed in the statistical analysis plan. We designed CARDIO-TTRansform to right information on the benefit of TTR lowering in a broad, diverse patient population that is representative of the evolving and dynamic ATTR cardiomyopathy treatment landscape. The large size of this international multicenter trial will allow us to analyze the effect of eplontersen in important subgroups of patients, such as hereditary or wild-type ATTR patients in patients on or naive to tafamidis. We expect to generate a robust data set that should enable physicians, patients and payers to meet the most informed decisions for patients with ATTR cardiomyopathy. We expect the complete enrollment for CARDIO-TTRansform form by midyear this year. Within CARDIO-TTRansform, we are also conducting additional profile enhancing imaging studies. The goal of these studies is to provide additional data to physicians and patients to help them make informed decisions. We expect the data we will generate in CARDIO-TTRansform will position eplontersen to successfully compete in the underserved dynamic in global ATTR market. The strong clinical trial results in ATTR polyneuropathy reinforce our conviction that eplontersen could provide similar benefit in patients with ATTR cardiomyopathy. With that, I will turn the call now over to Onaiza.

Thank you, Sam. Dr. Khella provided us with a vivid picture of patients with ATTR polyneuropathy, including the wide range of debilitating symptoms they suffer from and the dramatic impact this disease has on their daily lives. Based on eplontersen significant and sustained benefits demonstrated across all measures of these words, combined with the self-administered auto injectors, we believe that eplontersen is positioned to be an important new treatment halt neuropathy disease progression and for many ATTR polyneuropathy patients improve their neuropathy and quality of life. There are more than 40,000 estimated hereditary ATTR polyneuropathy patients worldwide including mixed phenotype patients who have both neuropathy and cardiomyopathy. Strikingly, fewer than 20% are currently receiving approved treatment. By combining our deep expertise in ATTR patient identification tools and rare disease marketing with AstraZeneca's global reach and commercial depth, we are uniquely positioned to penetrate and expand the virtually untapped ATTR polyneuropathy market around the world. At Ionis, we have made tremendous progress in building our commercial organization. We have hired top talent and integrated commercialization processes into the fabric of our operations. Today, we are finalizing preparations for the launch of each of our near-term products, starting first with co-commercializing eplontersen with AstraZeneca. Our joint team is working hand-in-hand with a shared global strategy to penetrate this dynamic market and bring eplontersen to patients with ATTR polyneuropathy following a potential U.S. approval in December. In preparation for launch, we have implemented the U.S. brand strategy, ensuring that we are ready to deliver a successful launch focused on product positioning with compelling messaging based on eplontersen strong efficacy and safety data. and a clear payer value proposition to ensure we are penetrating and expanding the market. We and AstraZeneca have also jointly prepared the U.S. tactical plan with robust medical, commercial and access initiatives, ensuring that we are utilizing the expertise of both organizations to expand the market and reach these underserved and often misdiagnosed patients. As we have discussed, the majority of ATTR polyneuropathy patients have mixed disease, and they will present in a number of different types of physician settings to reach as many patients as possible AstraZeneca's seasoned field teams, complementing Ionis' patient education managers are organized to reach into the community with the goal to accelerate diagnosis and treatment for patients in need. AZ's global scale and experience in commercializing cardiovascular medicines will also be key in enabling eplontersen to reach as many patients as possible as we move to the broader ATTR cardiomyopathy indication clinical approval. The majority of the infrastructure for the U.S. eplontersen launch is in place, and we are putting the finishing touches on our launch plan, ensuring we are launch ready by late this year. Based on the compelling Phase III results we shared today, we believe we have a strong product profile that should enable us to capture a significant portion of this multibillion dollar market. Our joint team is excited and ready to bring this important medicine to the market with clinically meaningful benefit to offer patients with ATTR polyneuropathy hopes to regain control of the most important aspects of their daily lots. With that, I'll turn the call back over to Brett.

Thank you, Onaiza. I'm pleased to say that the eplontersen program is firing on all cylinders. To reiterate what I said at the beginning of today's webcast, we are extremely pleased with the results we have seen with eplontersen to date. We firmly believe that its overall efficacy, safety and administration profile positions eplontersen to be an important new treatment or largely untapped ATTR polyneuropathy patient population. Additionally, these results further strengthen our confidence for a successful outcome in our ATTR cardiomyopathy Phase III study. Together with our partner, AstraZeneca, we believe that eplontersen has a strong product profile that, if approved, would provide patients with a new much needed treatment for TTR amyloidosis. We look forward to providing additional updates throughout the year on the progress we're making with the eplontersen program. Coming up in the second half, we look forward to presenting data from additional analysis, including the week 85 results as well as publishing the week 35 and week 66 results as soon as possible. We and AstraZeneca also continue to work towards additional regulatory submissions in countries outside the United States. In addition to these updates on eplontersen, we look forward to a number of additional updates from our robust cardiovascular and neurology franchises. With that, I'll now open the call up for questions. Jason?

[Operator Instructions] Our first question comes from Myles Minter from William Blair.

Congrats on the data here it looks like a very competitive profile to what's already on the market from one of your peers. Obviously, cross draw comparisons forward with our caveats yet, we do them anyway. So I'm referring to Helios and our future. I think one of the investor questions I think at Ionis is just when you look at the deltas, so the separation between drug and placebo across the different time scales here. It does appear to look at least a little bit numerically [ be go ] With them future than it does for the eplontersen data set. I know that there's different time points involved here. There's different placebo responses, different patient populations. I'm just wondering like how valid those cross-trial comparisons are in your point of view? And what the key sort of things are to look for in terms of differences in patient demographics that we might want to look for when we're interpreting these changes.

Myles, great question. Yes, you hit it on the mark where in the beginning of your comment. Doing cross-trial comparisons is totally inappropriate it's bad clinical science and is -- can be risky because you can drive different inappropriate conclusions. The delta difference between the efficacy that we showed in both the co-primary endpoints mNIS+7 and Norfolk Qualiy of life compared to placebo, the delta we showed was substantial. However, in our study in our placebo study, which was an external study, the patients were on the mild side compared to competitor programs. Therefore, they did not progress to the same extent as what we've seen out there with other programs. Therefore, it's not possible to show a greater delta than what we showed. We've actually halted the disease progression. And in fact, a substantial number of patients improved compared to their baseline entry values. You can't do much better than that. We have -- external placebo. That's what we are comparing our treatment effect, too, and that's about as best you can do. We're also very pleased with the fact that, especially in Norfolk Quality of life, our efficacy wasn't waning with time. In fact, we see further evidence of improvement with continued treatment, which I think is also pretty remarkable. And I'll just ask Onaiza, too. I mean, from a commercial standpoint, doing these cross-trial comparisons, in my view, is also irrelevant. Would you agree with that, Onaiza?

Yes. Thanks, Myles, for the question. And if I think about what's meaningful to clinicians and what's important in terms of the data that they're going to choose in terms of prescribing. One of the key areas that we see and the number one actually attribute is Norfolk Quality of life as well as halting disease progression. And the improvement that we can show for patients in these because our responder analysis is actually very important. And that is irrelevant or where kind of placebo started. And you really need to focus in on that in your promotion. And if you take a look at the promotion that's out there already for AMVUTTRA , as you mentioned, that's exactly where they're focusing as well. So none of their data is like looking at what the historical placebo for ONPATTRO was it's really looking at the level of improvement that the drug currently provides. And that is what's going to be most meaningful in the marketplace.

The next question comes from Yanan Zhu from Wells Fargo Securities.

And I wanted to add my congrats to the strong dataset you've demonstrated from neuro transform. I have a question in the AE table under the TEAE of special interest. So there, there is this item ocular events potentially related to vitamin A difficiency. There -- it seems like eplontersen arm has a higher rate, 27% compared with 15% for the external placebo, of course. Wondering, are these referring to clinical events or at least just lab values? And is this imbalance any cause of concern. Also, I just also wanted to mention, I don't think we've seen this imbalance in HELIOS-A study. So just wondering, is there any reason that the difference here?

Thanks, I'd like Eugene to comment on that.

Sure. Happy to. So yes, that -- it is a good question. What's important to clarify is that line in the AE table combines both treatment AEs of low vitamin A level and ocular events that are potentially related to low vitamin A level. If you split those two terms, the imbalance is driven predominantly by the former. So it's really the difference between low vitamin A levels in placebo and eplontersen arm. And of course, as you recall, TTR protein is the main carrier of vitamin A in blood. What's important to note is that all patients receive vitamin A supplementation. And as a result of that, there was no clinically meaningful sequela of potentially lower vitamin A levels in blood, not in tissues, but in blood. So again, the main conclusion is, it's a known kind of on-target liability that is managed by sort of easily managed by taking recommended daily doses of vitamin A. But as far as the actual ocular events, there is no imbalance between placebo and treated on.

Eugene, it might be also worth commenting on how vitamin A was measured and observed by investigators in the neuro transform study versus the original inotersen Phase III study. I think that's important.

Yes. It is important, Brett. Thanks for pointing that out. Of course, the NEURO-TTR, the historical study of inotersen was a blinded study. It was randomized one-to-one placebo or inotersen and blinded. And as a result, the levels of vitamin A were not available to investigators to react to or to see during the study to preserve that blind. This was not the case in the eplontersen transform study. it is an open-label study. And investigators were seeing all of the vitamin A data as the study was progressing. And in some instances, we're reacting to these low levels by considering them to qualify as adverse events. So again, there is potentially a reported bias, if you will. So that needs to be considered as well.

If you take out the vitamin A lab measurements and you look at ocular -- any kind of ocular vision problems, Yanan, and they're well balanced, equally down between placebo and treatment. It's really it's a lab measurement issue.

Got it. I see. Got it. That's very helpful. Maybe another question on how this dataset affects your confidence for the cardiomyopathy study? And when might we see the cardiac subgroup data from the NEURO-TTRansform study.

Sure. Great question. So we -- and I'll ask Sam -- Tsimikas, to comment on the CARDIO-TTRansform study. But in short, we strongly believe we have the right the most robust clinical trial design for TTR cardiomyopathy. We strongly believe that. And we believe that this trial design is necessary to ensure for the most successful outcome possible. We have a great trial design. Now we know we have a great drug with eplontersen. We have all the pieces to the puzzle to ensure for a highly successful outcome. We're -- it just gives us even greater confidence. Sam, do you want to add anything to that?

Well, I think you mentioned all the key fours. I just want to add my enthusiasm basically that we have a great drug a beautiful preamble to what we expect to see in CARDIO-TTRansform. We're going to knock on levels down and keep them down. We're going to have a great safety profile, and that should lead to excellent outcome considering the fact that we've had the opportunity to optimize the trial design, make it about twice as large as other studies, and we have lots of patients on and off tafamidis and with hereditary disease. So we feel very confident we're going to have a very rich data set and a great drug, and we look forward to the results when they come out.

The next question comes from Paul Mattias from Stifel.

This is James on for Paul. Congrats on the data. Maybe just a quick clarifying question. So the NDA was originally based on the 35-week data, right. So I'm wondering if -- does the FDA need to see the 66-week data? And is there any risk on trigger or amendment and cause any sort of approval delay? Any color there would be great.

Great question. The -- all the data that we believe will be necessary for the FDA to render their decision by December 23 is in front of the FDA today. That includes the week 35 efficacy data in the week 120 safety data. We have had no delays or any red flags in the review process to date. We do not plan to submit the week 66 efficacy data or additional data beyond the week 120 because we don't believe it's necessary and would only cause a delay in the approval process. And in fact, we don't believe we need it from a commercialization standpoint. Of course, we will use week 66 data for regulatory geographies where it's requested, it's required and that includes most of the countries ex U.S. But for the U.S., we don't need it. And we don't believe, as I said, we need it for to maximize success on the market. And maybe Onaiza could touch on what I mean by that.

Yes. I just wanted to amplify what Brett said, James, that you're seeing some really great data at week 66 and trends continuing to improve. So we are not limited in any way, not to be able to use the data, even though we submitted with the 35 week, which was very strong. So as long as we're going forward with a publication, which is right on track, we will be able to use the data from both the 35-week as well as the 66-week efficacy data in promotion based on regulatory guidelines we have from [ OPTP ].

The next question comes from Debjit Chattopadhyay from Guggenheim Partners.

I have two. Number one, in the APOLLO-B study, there was no benefit of adding a silencer on top of stabilizer. What are the implications for silencers if this observation is repeated in the HELIOS-B study? And the second question, with eplontersen while platelet monitoring is no longer required across any of your studies, did its Q initial enrollment in CARDIO-TTRansform to more advanced or towards healthier patients. Congrats on the data and the approval for tofersen.

Thanks, Debjit. Sam, would you like to address the question...

Yes sure. That's a great question. I think we have to keep a [ whole of B ] in mind that it wasn't designed as a outcomes trial, so it's underpowered from that perspective. It also wasn't really designed to be able to tell you who was on and off the [indiscernible] and how the outcome would be. And remember that the primary endpoint was 6-minute walk test. So we're talking about very different end points in an outcomes trial that we're doing versus that study. So with that in mind, I think just from epiphysiology perspective, when you have a way to knock out the problem in the liver, it makes intuitive sense that, that would be better than stabilizing it or at least equal or better. And so ultimately, I think you want to address the problem at the root cause, which is that the liver makes and then it misfolds. So that's what the silences will be doing. And we think that ultimately needs to be confirmed, but that you can make a strong case that would be the issue in terms of it being a better approach. On your second question on the platelets, the platelet exclusion issue doesn't really exclude patients that are ill from TTR cardiomyopathy. That's really a separate issue to have a baseline platelet abnormalities you usually do it to another cause that's unrelated to the primary endpoint. So our platelet count entry is 125 or above, so it's actually below normal. But that shouldn't affect the anything has to do with cardiac issues. So we don't think we're missing out on any kind of patients in terms of the primary endpoint that we're testing based on that platelet issue. And of course, as you saw from the polyneuropathy study, nobody got under 10,000 and these were transient reductions. So we don't think the platelet issue ultimately will be a problem in cardiomyopathy trial either.

Next question comes from Mike Ulz from Morgan Stanley.

And maybe just to start, a quick follow-up on an earlier question related to the 66-week data. Just given the strength of that data, any potential plans to maybe add it to the U.S. label at a later date?

Yes. Thanks for following up on that. I mean to follow up with the Onaiza's great response earlier. We always have that option, Mike. If we feel that it's valuable to significantly valuable to add additional data based on the week 66 data to the label for the U.S. market. We can do that through a supplemental NDA. The real question comes down to is whether it will be worth the time and effort to do so. And Onaiza said, we're really not -- we're not in any way in an inferior position to be able to promote the week 66 data for all the reasons she went into on the U.S. market. So we have to balance that versus all of the other regulatory filings, that we have from our -- in AstraZeneca's regulatory group. We have a lot of work ahead, right? We're going to be filing in Canada soon. We're going to be filing in Europe in multiple countries this year. we got our eyes on China. We got our eyes on Japan. We got our eyes on [ LatAm ] , and there's a lot to do there. So it's got to really be worthwhile for us to do so. But if we find -- if we feel that it's worthwhile, we have that option to do it for a supplemental NDA.

Yes, I just wanted to just follow up with Brett also is that the priorities in the other markets are also really important. And keep in mind, we just got out of AstraZeneca meeting I did anyway this morning, and we were going through all the regulatory filings we're going to be actually first in many markets. So we really want to keep that first lead as well, and we don't believe that is going to compromise our promotional position in the U.S. at all. But we certainly have that opportunity.

Got it. Makes sense. And maybe I could just ask a quick question to Dr. Khella. Maybe you can just comment on from a patient's perspective, having the ability to self-administer how important will that be for some of your patients?

Sure. I think a lot of these patients are very debilitated and don't want to be going to a doctor's office, especially when they live very far away from the amyloid center that they are being treated at. And so having the convenience of an injection performed at home is huge.

The next question comes from Gena Wang from Barclays.

Hello. This is Xu on for Gina from Barclays. Congratulations on the data readout. I have two questions. First one, maybe I missed in your previous answer, just excuse me for that. So what additional data update from NEURO-TTRansform should we expect throughout 2023. Would the update include any exploratory cardiac biomarkers?

No, we didn't address that already, so you didn't miss it. Yes, we plan on sharing. We just haven't analyzed all the data. This is a very robust data set that we shared through various forms, including this webcast this week, but it's top line data, and we have more data to analyze. That will include exploratory endpoints, including cardiac endpoints, endpoints related, for example, imaging endpoints related to cardiac amyloid buildup, walk test, gate speed, additional biomarker data that is related to the neurological disease progression and cardiomyopathy disease progression. So stay tuned for additional data this year, and we're looking forward to sharing it as soon as we analyze it and can get it out. And as I also mentioned earlier, we're putting the final touches on some publications. We're very enthusiastic to publish and to publish in a top-tier journal that's -- well, that's very extensively peer reviewed. So whether we get some of that data in there or not is to be determined, but we'll certainly get that data out this year.

My second question, I want to follow up with Dr. Khella. So what's going to be the ideal target patient profile for eplontersen? Like what type of patients do we think are going to prefer eplontersen, like age or disease stage, et cetera? And also under your practice, what percentage of the patients do you think going to choose eplontersen? If you can give us a number, that will be helpful.

Sure. Thanks for the question. I think this is a drug that's going to be effective in a broad range of patients from those who are minimally symptomatic to those who have more advanced disease. As I mentioned previously, this is a fatal disease. And any time you can slow down the progression of the illness, presumably, this will prolong life. I think patients will be accepting a medication like this. I think a large number of patients would be -- this drug would be useful for. As I said, I have many patients who come from far away and don't want to travel 5 or 6 hours by car to come get an injection and go back home. So I would expect that a drug that has a very safe profile to be given to a large number of people in my practice.

The next question comes from Yale Jen from Laidlaw & Company.

My congrats on a great data. I have 2 here. The first question is that for the Phase III study that you do have in a person portion patients. And just curious whether their data readout is any different from the person part of the study? And then I have a follow-up.

Thanks, Yale. I'll ask Eugene to talk a little bit about the inotersen data and maybe the timing once we get it analyzed, when we might share it or something like that.

Sure. Yes, happy to. Yes. So really, the intention of a small inotersen arm, as I said, it was a much smaller arm of only 24 patients, so we had 6 to 1 randomization was really to provide that bridging -- small bridging data set to the original NEURO-TTR study. This was requested by regulators and that's why it was built into the design. But really, the goal is to qualitatively assess sort of comparability to the population that was enrolled in NEURO-TTR. And again, there is no intention of any formal statistical comparisons because of the size of that data set.

What I'll just add to what Eugene said is that what we did see is that we expected to see what we see with our LICA platform in general, is substantially greater reductions in TTR levels compared to inotersen, and I think that's reflected in the greater efficacy and the improvements in clinical performance of the patients that are being treated with eplontersen. And, of course, better tolerability and better compliance, patients with virtually -- patients were dropouts were below in the eplontersen arm, certainly below the inotersen arm and on a percentage basis and even below that of placebo from the historical control. So do you have -- Yale, do you have a second question?

In terms of the mixed type patients in this study, did you guys gave out a sort of percentage at this point? Or should we anticipate that in the future?

We have not yet. It's a percentage of patients with mixed phenotype that is below 50% about in the study. We still have a sizable number of patients with cardiomyopathy involvement. And as I said earlier, when we analyze that data, we're looking forward to sharing it.

The next question comes from Salveen Richter from Goldman Sachs.

This is Shrunatra on for Salveen. And congratulations on the data. So there are 2 questions from us. The first is, how are you thinking about relatively flat mNIS+7 curve, where you see a clear continued decrease on Norfolk Quality of Life. And the second question would be on the commercial strategy front, I mean, in terms of early adopters and strategies for patient identification?

Yes. Great question. I'll ask Eugene to talk a little bit about -- and maybe even Dr. Khella could also talk about what is it about neurological disease progression in which we're flatlining the progression based on mNIS+7 and why that might translate to even better efficacy as measured by Norfolk Quality of Life instrument. Again, in both instances, in both endpoints, we're seeing a substantial number of patients improving. But the mean the LSM is flat for mNIS+7 and clearly is below baseline for Norfolk Quality of life. So which one of you gentlemen who like to jump in there first?

Sure. I can talk about the patients feeling better when they had been expecting their neuropathy to progress as it had been for a number of years prior to diagnosis and then it stops progressing. They don't feel more pain, they don't have more weakness, they don't have more clumsiness. They're able to do things for themselves when they were expecting not to be able to do that. It makes people feel a lot better. So I think that's a dramatic finding in this trial.

Eugene?

No, not really. Again, it's probably not unique to this illness. Every time you have progressive disease associated with loss of independence and loss of milestones that kind of expectation is that, that's going to continue and patients are really disturbed by that. But once you stop that progressive nature, obviously, their quality of life as reported is much improved. So there's no -- in my mind, there is no disconnect. It's almost kind of the expectation.

Thanks, and Onaiza, would you like to comment on the second part.

Yes. Thanks for the commercial question on early adopters. So it's really interesting in that we obviously have a lot of experience from first generation to know where some of the core centers of excellence are that will house a lot of patients that have already been treated. And that's going to be important in our mix, right? But we're really doing both. And I think with the strength of a partner, we can have and versus an or here. Because oftentimes, when you go into launch, you kind of go early adopter first, then your next set and then your third set of later adopters, but we're actually doing both. We went through our launch strategy earlier, and we have our core centers of excellence, and we have the broader centers of excellence that we're already trying to develop and mine and get them aware of these patients. Like I said, we've only penetrated less than 20%. And we're also thinking about the community. There are a lot of physicians in community neurology as well as community cardiology that prescribe. So we're doing kind of all 3 phases at once, and we can do that when we have 2 companies going at market really beautifully well. We also think that's the best way to get the -- to get to the full potential of the drug, but also these underserved patients that are out there that haven't been diagnosed and treated. So no need to kind of focus only on switches, but really expansion of market.

Next question comes from Joseph Stringer from Needham & Company.

This is [ Barbara ] on for Joey. And our question is for Dr. Khella. So Dr. Khella, in terms of clinical data, what's the top 3 that you would consider when [ thinking of ] TTR silencer in a patient? And kind of as a follow-up question, eplontersen is a once-monthly injection versus a motor, which is once every 3 months? And how big of a deal is this do you think for patients and physicians.

Sure. So obviously, a drug that will stop the progression of a neuropathy is primary in my consideration, and presumably, that will translate into prolonging life, improving quality of life as well. And then in terms of once a month and once every 3 months, I think that's really not a significant factor in a patient's consideration when they have a fatal illness that had been previously untreated when they've seen many of their family members die without treatment. So now that they have these 2 drugs, I think it depends on the availability of the drugs for these patients.

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

This is Chi on for Jason. So I guess my question maybe for Dr. Khella, what's your overall view of the efficacy and safety profile of eplontersen relative to the RNAi approved therapies out there for polyneuropathy. And I guess for Dr. Khella and the company as well, do you think there's going to be any safety or monitoring requirement similar to TEGSEDI? Or do you think the label is going to be closer to vutrisiran with [indiscernible] being the only notable warning on the label.

Well, I'm happy to take the second part of the question. We don't expect any unusual monitoring in the label for eplontersen. The drug has shown remarkable safety across both the NEURO-TTRansform, the CARDIO-TTRansform study, the Phase I study. There's no evidence of any of the baggage that has been linked to inotersen earlier generation molecule, that has dosed at 20- to 30-fold higher doses compared to eplontersen. We don't expect anything unusual in the label with respect to monitoring period. And what was the first part of your question, which I think you directed it to Dr. Khella.

Yes. I was just wondering if the doctor's view on the overall efficacy and safety profile of eplontersen relative to RNAi targeted products. I'm wondering if the doctors see it as similar? Or is there anything that is uniquely different between eplontersen and RNAi targeted therapy that you would like to highlight?

No. I mean you saw the safety data that was presented. It was great. It looks like a very well-tolerated drug without any real safety concerns. So I don't have any concerns about it.

And efficacy.

Well, the efficacy speaks for itself. We -- the study has shown that the drug is very effective. And when you look at the patients who have amyloid doses, they -- it's a relentlessly progressive disease. And it's a systemic disease. So it's not only the neuropathy, it's everything else that goes -- that's indirectly measured in the quality of life that was not explicitly measured in just the mNIS. So my deduction is that this drug improves systemic well-being in addition to just the neuropathy.

Next question comes from Kostas Biliouris from BMO.

A couple of questions from us. The first one is whether you have performed any analysis so far to assess the intra-patient correlation between the different endpoints that you presented today and if you could identify any characteristics there of patients who may respond better? And the second one is whether the difference between the reduction in TTR from eplontersen and other drugs in the space is meaningful in your view? Or is not that important? Sorry if I missed this point, but my line was dropped a couple of times.

No problem. Thanks, Kostas. So I could turn it over to Eugene to address the clinical question, but there's not much to say. We look forward to deep -- doing a deep dive into the data more and we will look at individual patient, and we'll do everything we can just to learn more about the science behind TTR amyloidosis in the pharmacology of eplontersen. We'll look at the relationship between TTR lowering on the individual patient and in clinical response. What we will look at the same for -- on an individual basis, the correlation between mNIS+7 and Norfolk Quality of Life on an individual basis. We'll do all that work, but we just don't have that data today. As far as reduction in TTR, there is evidence that the greater you reduce TTR, the greater the efficacy. What we don't know and there's no evidence for today is whether there's a threshold minimum level of TTR reduction that's necessary to show efficacy or whether there's a ceiling effect that once you get to a certain point, you've maxed out on your efficacy. We will do all the analyses we can possibly do to better understand the pharmacology and the biology behind the eplontersen in TTR amyloidosis, but we don't have that data now, that will be coming. So -- and then finally, TTR reduction is very important. It's very important. It is the root cause to be able to show and speak to in your label. We showed a mean reduction of 82% plus reduction of TTR in this study, that is very competitive. And it's important to have that in our label because we all know that TTR is the root cause of this disease. So it would be very important to be able to discuss that, present that, talk about that with patients and physicians. Thanks for the question, Kostas.

The next question comes from William Pickering from Bernstein.

Congrats on the data. I was wondering for the CARDIO-TTRansform study, if you could describe the considerations beyond blinded event rate that would inform your decision to have an early readout and when you're thinking about might be the right time to make that decision?

Sam, would you like to...

Yes. So the study of design right now goes up to a maximum of 140 weeks, but we've built into our statistical analysis plan some possibilities for earlier looks, certainly blinded event rates will be one, but also looking at the other trials that are going to be reading out and looking at their event rates. So that's also part of it. So the bottom line is it's a little early to make that call right now, but we're going to look at all evidence available for us before we can make that call.

Thanks, Sam. And I'll just add to that. The enrollment is -- when we upsized enrollment last year, we had several objectives to accomplish. One was to ensure that we had the right powering for the patient demographics that exist today for TTR cardiomyopathy, a demographic that is very different than the tafamidis ATTRACT study. Patients are milder and therefore, we upsized the study to 1,400 patients, and we're looking forward to completing enrollment very soon in that study. We also sought to ensure that we had a good balance of tafamidis used in that study, in naive patients in that study. So we can make claims when data reads out the benefit on top of a stabilizer as well as in naive patients. That's a rich data set that's very important for commercial success, maximize commercial success. We also did that to increase the percentage of patients in the study that have hereditary TTR cardiomyopathy, very important, these patients generally are sicker than the wild-type patients. And as I said, a good balance between tafamidis usage in naive patients was very important for us to achieve too. I'm very pleased to say that we are accomplishing all of our objectives for the upsizing of the study. All 3 of those objectives are well in sight and we think that we're going to have them well accomplished when complete enrollment soon.

The next question comes from Yaron Werber from Cowen.

This is Brendan on for Yaron. Just a couple of quick ones just kind of building on some of the earlier questions about the launch. As you kind of look ahead a little bit to cardiomyopathy, are there physicians or centers that you've already identified or planned to, that you think would be especially attractive that you could target any initial PM launch, but maybe sets you up for success later on. Just trying to get kind of a feel on how that strategy plays into effect here. And then also, just really quickly, do you see any option or have any intention either through OLE or a separate study to consider longer dosing intervals? Is this something you could potentially study in real-world setting? Or would you expect physicians to kind of stick to the strict monthly dosing regimen?

Yes. I'll definitely take the first part of the question. So I think that we're using a tremendous amount of data and insights that are available now that weren't a few years ago as we figure out our launch strategy. We're thinking about the types of physicians that actually care about the mixed phenotype. Not only do they have them in their practice, whether they care enough to treat about it. And we can do that with a little bit with our AI tools. We just went through kind of the tools that AZ has already developed. So there will be an identification of the types of physicians that have the mixed phenotype patients already presenting in their office and ones that they choose to treat versus referring them back out. So yes, we will be there. And as we get more and more into the polyneuropathy launch leading to the cardiomyopathy given how Dr. Khella described, it's a systemic disease and can show up really anywhere in the body, that's really one of our approaches is to set kind of the franchise up for the systemic nature of the disease and get to those physicians that think about it that way and create more physicians awareness around the systemic nature of the disease and that what should they be looking for. So it's a really big part of our approach.

Yes. And to address the second part of the question, would we -- do we have the option to look at less frequent dosing. First, I want to highlight what Dr. Khella said, he doesn't see an advantage between monthly versus 3 months for this severe, terrible disease, especially -- and then Onaiza's comments earlier that an at-home, self-administered auto-injector is a big advantage for these patients, as Dr. Khella also highlighted. And that really very much overrides, if you will, any advantage for slightly less frequent dosing in our view. We have highlighted today why AstraZeneca is such a great partner for eplontersen. We've highlighted several reasons, including the global reach and first to market in several geographies, utilizing the tremendous resources and expertise that AstraZeneca has along with the expertise that Ionis has in TTR amyloidosis. But I'd also add that we -- to address your question is we have a life cycle management plan that is being developed. Stay tuned for that. We're not ready to talk much about that, but I wouldn't rule out any of these -- any options to further enhance the profile, the dosing profile and other aspects to generate more data for eplontersen in the future. Stay tuned for that. And that is the last question for today's webcast. We really appreciate everyone joining us today. We're confident we are on the path to changing the way patients with ATTR amyloidosis are treated with eplontersen. However, before I let everyone go, I want to reward those that stuck on to the bitter end by saying -- informing you with great joy the great news we are now reporting today that the FDA has approved Biogen's NDA for Qalsody, formerly known as tofersen, for the treatment of SOD1 ALS, making it the first and only disease-modifying therapy approved for a genetic form of ALS. Its approval was a turning point for SOD1 ALS patients, their families and caregivers and has the potential to transform the way future ALS drugs are developed and importantly Qalsody follow SPINRAZA as the second RNA-targeted therapy from our pipeline, a pipeline that has 12 medicines in development today for CNS diseases, that our next drug to be approved for CNS diseases for a rare, deadly neurological disease. Thank you all again. We look forward to sharing more data and more updates on Qalsody as the year unfolds. But for now, that's all we have. Thanks again for joining us for today's call, and have a great afternoon.

Conference has now concluded. Thank you for attending today's presentation. You may now disconnect.