Good afternoon, welcome to Ionis's 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 Walk, Senior Vice President of Investor Relations, to lead off the call. Please begin.
Thank you, Jason. Hello, 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 investor 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 two, which contains our forward-looking statement. 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 Cardio-TTRansform study. Onaiza Cadoret-Manier, Chief Global Product Strategy and Operations Officer, will provide an update on our pre-commercial preparations. 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-TTRansform study at AAN yesterday. We're happy to have him with us to discuss the eplontersen results and to be on hand to answer our questions. With that, I'll turn the call over to Brett.
Thanks, Wade. 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 TTR amyloidosis, 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 four secondary endpoints, further reinforcing eplontersen's 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 Cardio-TTRansform study. Based on these strong data, together with at home self-administration with an auto-injector, we believe, if approved, 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 the clinicians who have participated in the NEURO-TTRansform study and contributed to the positive results we are reporting this week. 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 to those in the ATTR community whose 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
Inhibit the production of TTR protein, the root cause of TTR amyloidosis, also known as ATTR. We're developing eplontersen for two indications: hereditary ATTR polyneuropathy and ATTR cardiomyopathy. In a few moments, Sam will discuss our ATTR cardiomyopathy development program and its current status. First, let me remind you of the design and objectives of NEURO-TTRansform. The phase III NEURO-TTRansform study is a global, randomized, open label study that enrolled 168 adult patients with stage 1 or stage 2 ATTR polyneuropathy. Patients were randomized in a 6-to-1 ratio to either 45 milligrams of eplontersen administered once monthly or 300 milligrams of inotersen administered once weekly. 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. 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 eplontersen. At the week 35 interim analysis, the study had two co-primary endpoints: TTR reduction and a change in modified neuropathy impairment scale, or mNIS+7 composite scale. At week 66, we included an additional co-primary endpoint, 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, i.e. during trough, which means that the TTR reductions likely represent the most conservative estimate. 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, where 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 analyses from NEURO-TTRansform.
Thank you, Eugene. TTR amyloidosis, or ATTR, is a systemic it's a rapidly progressive debilitating inherited disorder. It's inherited as an autosomal dominant fashion, 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 nervous system, leading to early erectile dysfunction, 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 their diagnosis. The delay in diagnosis becomes a problem in treating these patients 'cause 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 walk very well, have activities, problems with activities of daily living. it can be quite a.
Goodbye.
Pardon me, everyone. It looks like our speaker line has disconnected. Please hold while we reconnect.
Hi, we're back. Can you hear us?
Yep. I can hear you come in loud and clear.
As I said, this is a progressive and fatal illness. As Eugene reviewed, the NEURO-TTRansform 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-TTRansform were also consistent with the 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-TTRansform, consistent with what we're seeing in the current treatment landscape. There were slightly more eplontersen-treated patients with V30M mutations 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. 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 -9 points at week 35 and -25 points at week 66. Over time, the placebo group's mean mNIS+7 got progressively worse as their disease progressed. In contrast, the 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. Moving to the Norfolk Quality of Life score. Here again, eplontersen-treated patients showed a 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. As with mNIS+7, a majority of the eplontersen-treated patients also showed improvement in their quality of life compared to their base values. At week 66, Norfolk scores improved from baseline in 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 received stabilizer treatment prior to entering the study. 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 endpoints measured 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 benefit 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. 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. To summarize the findings from NEURO-TTRansform, eplontersen demonstrated a consistent and sustained benefit across all primary and secondary endpoints. The consistency in efficacy data is compelling.
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 years-5 years from disease onset. ATTR cardiomyopathy includes both the genetic 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. The favorable safety and tolerability profile that we have seen in ATTR polyneuropathy patients in the NEURO-TTRansform 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. A reminder, Cardio-TTRansform is expected to enroll approximately 1,400 patients. The primary efficacy endpoint is a composite of cardiovascular death and recurrent cardiovascular events.
The study is designed to have a maximum, 140 week treatment duration. 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 provide 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 multi-center trial will allow us to analyze the effect of eplontersen in important subgroups of patients such as hereditary or wild type ATTR patients, and patients on or naive to tafamidis. We expect to generate a robust data set that should enable physicians, patients and payers to make the most informed decisions for patients with ATTR cardiomyopathy. We expect to complete enrollment for Cardio-TTRansform by mid-year 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 and 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's significant and sustained benefit demonstrated across all measures of disease burden, combined with the self-administered auto-injector, we believe that eplontersen is positioned to be an important new treatment to halt neuropathy disease progression. 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 this largely 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's 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 with clinical approval. The majority of the infrastructure for the US eplontersen launch is in place, and we are putting the finishing touches on our launch plans, ensuring we are launch-ready by late this year. Based on the compelling phase III results we share today, we believe we have a strong product profile that should enable us to capture a significant portion of this multi-billion 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 hope to regain control of the most important aspects of their daily lives. 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 for a largely untapped ATTR polyneuropathy patient population. 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 analyses, 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 floor up for questions. Jason?
Thank you. We'll now begin the question and answer session. To ask a question, you may press star then one on your touch tone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. At this time, we'll pause momentarily to assemble our roster. Our first question comes from Myles Minter from William Blair. Please go ahead.
Hi, everyone, 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-trial comparisons flawed with caveats, yet we do them anyway. I'm referring to HELIOS-A and AMVUTTRA. I think one of the investor questions I've been getting is just when you look at the deltas, so the separation between drug and placebo, you know, across the different timescales here, it does appear to look at least a little bit numerically bigger with AMVUTTRA than it does for the eplontersen dataset. You know, 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? Thanks very much.
Thanks, Myles. Myles, a great question. Yeah, you hit it on the mark right in the beginning of your comment. Doing cross trial comparisons is totally inappropriate. It's bad clinical science and can be risky because you can draw different inappropriate conclusions. You know, the delta difference between the efficacy that we showed in both co-primary endpoints, mNIS+7 and Norfolk quality 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 an external placebo. That's what we're comparing our treatment effect to, 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. I'll just ask Onaiza too, I mean, from a commercial standpoint, doing these cross trial comparisons, in my view, is also irrelevant.
Yeah.
Onaiza, would you agree with that, Onaiza?
Yeah, thanks, Myles, for the question. you know, if I think about what's meaningful to clinicians and, you know, 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. The improvement that we can show for patients in these, which is our responder analysis, is actually very important. That is, that is irrelevant to where kind of placebo started. You really need to focus in on that in your promotion. 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.
You know, 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.
Thanks, Myles.
The next question comes from Yanan Zhu from Wells Fargo Securities. Please go ahead.
Hi. Thanks for the question, I wanted to add my congrats to this strong data set you've demonstrated from NEURO-TTRansform. I have a question in the AE table under the AE TEAE of special interest. There is this item, ocular events potentially related to vitamin A deficiency. 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 are these just lab values? Is this imbalance any cause of concern? Also, I just wanted to mention, I don't think I've we've seen this imbalance in HELIOS-A study.
Just wondering, is there any reason, the different, the difference, here?
Thanks, Yanan. I'd like Eugene to co-comment on that.
Sure, happy to. Yanan, it is a good question. What's important to clarify is that that line in the AE table, it 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. It's really the difference between low vitamin A levels in placebo and eplontersen arm. As you recall, TTR protein is the main carrier of vitamin A in blood. What's important to note is that all patients received 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.
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. As far as the actual ocular events, there is no imbalance between placebo and treated arm.
Eugene, it might be also worth commenting on how vitamin A was measured and observed by investigators in the NEURO-TTRansform study versus the original inotersen phase III study. I think that's important.
Yeah, 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 1-to-1 placebo for inotersen and blinded. 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 NEURO-TTRansform 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 were reacting to these low levels by considering them to qualify as adverse events. Again, there is potentially a, you know, a reporter bias, if you will. 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 or vision problems, Yanan, they're well balanced, equally balanced between placebo and treatments. Really, it's a lab measurement issue.
Got it. I see. Got it. That's, that's very helpful. Maybe another question on how this data set affects your confidence for the cardiomyopathy study, and when might we see the cardiacs subgroup data from the NEURO-TTRansform study? Thank you.
Sure. Great question. I'll ask Sam, Sami to comment on the Cardio-TTRansform study. In short, we strongly believe we have the right, the most robust clinical trial design for TTR cardiomyopathy. We strongly believe that. 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, where it just gives us even greater confidence. Sam, you wanna add anything to that?
Well, I think you mentioned all the key points. I just wanna add my enthusiasm, basically, that we have a great drug. This is a beautiful preamble to what we expect to see in Cardio-TTRansform. We're gonna knock the levels down and keep them down. We're gonna 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 2 times as large as other studies, and we'll have lots of patients on and off the tafamidis and with hereditary disease. We feel very confident we're gonna have a very rich data set and a great drug, and we look forward to the results when they come out.
Thanks, Sam. Thanks, Yanan.
Great. Thank you.
The next question comes from Paul Matteis from Stifel. Please go ahead.
Great. Thanks. This is James on for Paul. Congrats on the data. Maybe just a quick, you know, clarifying question. The NDA was originally based on the 35 week data, right? I'm wondering if, you know, does the FDA need to see the 66 week data? Is there any risk it could, you know, trigger a major amendment and cause any sort of, you know, approval delay? Any color there would be great. Thanks.
Great question. The all the data that we believe will be necessary for the FDA to render their decision by December 23rd is in front of the FDA today. That includes the week 35 efficacy data and 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. In fact, we don't believe we need it from a commercialization standpoint.
Of course, we will use the week 66 data for regulatory geographies where it's re-requested, it's required, and that includes most of the countries ex-U.S. For the U.S., we don't need it, and we don't believe, as I said, we need it for, you know, to maximize success on the market. Maybe Onaiza could touch on what I mean by that.
Yeah. I just wanted to amplify what Brett said, James, that, you know, you're seeing some really great data at week 66 and trends continuing to improve. 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. 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 the OPDP.
Thanks, Onaiza.
Very helpful. Thank you.
Thanks, James.
The next question comes from Debjit Chattopadhyay from Guggenheim Partners. Please go ahead.
Hey, good afternoon. Thanks for taking my question. I have two. Number one, in the APOLLO-B study, there was no benefit of adding a silencer on top of a stabilizer. What are the implications for silencers if this observation is repeated in the HELIOS-B study? 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? Thanks so much and congrats on the data and the approval for tofersen.
Thanks, Debjit. Sam, would you like to address the question.
Yeah, sure. That's a great question. I think we have to keep APOLLO-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 know, who was on and off the tafamidis and how the outcome would be. Remember that the primary endpoint was six-minute walk test. We're talking about very different endpoints in an outcomes trial that we're doing versus that study. With that in mind, I think just from pathophysiology 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.
I think, you know, you want to address the problem at the root cause, which is that the liver makes it and then this folds. That's what the silencers will be doing, and we think that ultimately needs to be confirmed. That, you know, 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 abnormality is usually due to another cause that's unrelated to the primary endpoint. You know, our platelet count entry is 125 or above. It's actually below normal.
That shouldn't affect anything that has to do with cardiac issues. We don't think we're missing out on any kinds of patients in terms of in the primary endpoint that we're testing based on that platelet issue. Of course, as you saw from the polyneuropathy study, nobody got under 100,000, and these were transient reductions. We don't think the platelet issue ultimately will be a problem in cardiomyopathy trial either.
Thanks, Sam. Thanks, Debjit. Next question.
Next question comes from Michael Ulz from Morgan Stanley. Please go ahead.
Hey, guys. Thanks for taking the question. 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 US label at a later date?
Yeah, thanks for following up on that. I meant to follow up with Onaiza's great response earlier. We always have that option, Mike. If we feel that it's valuable, 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 it comes down to is whether it's, it will be worth the time and effort to do so. As Onaiza said, we're really not, we're not, you know, 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.
We have to balance that versus all of the other regulatory filings that we have from our and AstraZeneca's regulatory groups. We have a lot of work ahead, right? We're gonna be filing in Canada soon. We're gonna be filing in Europe, 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. It's got to really be worthwhile for us to do so. If, you know, if we feel that it's worthwhile, we have that option to do it through a supplemental NDA.
I just wanna follow up with Brett also is that the priorities in the other markets are also really important. 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 gonna be actually first in many markets, you know. We really wanna keep that first lead as well. We don't believe that this is gonna compromise our promotional position in the U.S. at all. We certainly have that option if we need to.
Got it. Makes sense. 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 would that be for some of your patients? Thanks.
Sure. You know, I think, a lot of these patients are very debilitated and don't wanna be going to a doctor's office, especially when they live very far away from, the amyloid center that they are being treated at. Having the convenience of, an injection, performed at home, is huge.
Great. Thank you.
Thanks, Mike.
The next question comes from Gena Wang from Barclays. Please go ahead.
Hello, this is Huidong. I'm for Gena from Barclays. Congratulations on the data readout. I have two questions. First one, maybe I'm missing your previous answers. Just excuse me for that. What additional data update from NEURO-TTRansform should we expect throughout 2023? Would the update include any exploratory cardiac biomarkers?
Thanks, Huidong. No, we hadn't addressed 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. It's top-line data, and we have more data to analyze. That will include exploratory endpoints, including cardiac endpoints related, for example, imaging endpoints related to cardiac amyloid buildup, walk test, gait speed, additional biomarker data that is related to neurological disease progression and cardiomyopathy disease progression. 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.
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. 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.
Thank you. My second question, I want to follow up with Dr. Khella. What's gonna be the ideal target patient profile for eplontersen? Like, what type of patient do you think gonna prefer eplontersen, like age or disease stage, etcetera? Under your practice, what percentage of the patient do you think gonna choose eplontersen? If you can give us a number, that'd 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. Anytime you can slow down the progression of the illness, presumably this will prolong life. I think patients will be accepting of a medication like this. I think a large number of patients would be this drug would be useful for. You know, I, as I said, I have many patients who come from far away and don't want to travel five or six hours by car to come get an injection and go back home.
you know, I would expect that a drug that has a very safe profile, to be given to a large number of people in my practice.
Thanks, Sami.
Thank you.
Thank you.
The next question comes from Yale Jen from Laidlaw & Company. Please go ahead.
Hello, good afternoon, thanks for taking the questions, and 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 inotersen portion, patients, and just curious whether their data readout any different from the eplontersen part of the study. 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. Yeah, happy to, Yale. 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 in, you know, 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. Really the goal is to qualitatively assess sort of comparability to the population that was enrolled in NEURO-TTR. Again, there's 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 what we expected to see, what we see with our LICA platform in general, is substantially greater reductions in TTR levels compared to inotersen. I think that's, you know, reflected in the greater efficacy and the improvements in clinical performance of the patients that are being treated with eplontersen. Of course, better tolerability and better compliance. Patients were virtually, you know, 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. There you have it, Yale.
Okay.
Did you have a second, you had a second question?
Maybe the one follow-up.
maybe, Yale, just to also clarify.
Follow-up question here is that, in terms of the mixed type patients, in the disc study, did you guys give 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. As I said earlier, when we analyze that data, we're looking forward to sharing it.
Okay, great. Thanks a lot, and again, congrats.
Thanks, Yale.
The next question comes from Salveen Richter from Goldman Sachs. Please go ahead.
Hello, team. Thank you so much for taking my question. This is Srinathra on for Salveen. Congratulations on the data. There are two questions from us. The first is, how are you thinking about the relatively flat mNIS+7 curve, where you see a clear-cut new decrease on Norfolk Quality of Life? The second question would be on the commercial strategy front in terms of early adopters and strategies for patient identification.
Yeah, 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, you know, we're flatlining the progression, based on mNIS+7, and why that might translate to even better efficacy as measured by
Neuro-QoL instrument. In both instances, in both endpoints, we're seeing a substantial number of patients improving, the mean, the LS mean, is flat for mNIS+7 and clearly is below baseline for Neuro-QoL. Which one of you gentlemen would 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. I think that's a dramatic, you know, a dramatic finding in this, in this trial.
Yeah. Did you?
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 gonna continue, and patients are, you know, really disturbed by that. Once you stop that progressive nature, obviously their quality of life as reported is much improved. There's no... In my mind, there's no disconnect. It's almost kind of the expectation.
Thanks. Onaiza, would you like to comment on the second part?
Yeah. Thanks for the commercial question on early adopters. It's really interesting in that, you know, 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. That's gonna be important in our mix, right? We're really doing both. I think with the strength of a partner, we can have an and versus an or here. 'Cause oftentimes when you go into launch, you kind of go early adopter first, then your next set, and then your third set of, you know, 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 in mind and get them aware of these patients. Like I said, we've only penetrated less than 20%. We're also thinking about the community. There are a lot of physicians in community neurology as well as community cardiology that prescribe. We're doing kind of all three phases at once, and we can do that when we have two companies going at market really beautifully well. We also think that's the best way 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.
No need to kind of focus only on, you know, switches, but really expansion of market.
Thanks, Onaiza. Next question.
Next question comes from Joseph Stringer from Needham & Company. Please go ahead.
Good morning. This is Barbara on for Joseph, thank you so much for taking our question. Our question is for Dr. Khella. Dr. Khella, in terms of clinical data, what's the top three that you would consider when treating TTR amyloidosis in a patient? Kind of as a follow-up question, eplontersen is a once monthly injection versus AMVUTTRA, which is a once every three months. How big of a deal is this, do you think, for patients and physicians? Thank you.
Sure. Obviously, a drug that will stop the progression of a neuropathy is primary in my consideration. Presumably that will translate into prolonging life, improving quality of life as well. In terms of once a month and once every three months, I think that's really not a significant factor in a patient's consideration when they have a fatal illness that has been previously untreated when they've seen many of their family members die without treatment. Now that they have these two drugs, I think it depends on the availability of the drugs for these patients.
Thank you.
The next question comes from Jason Gerberry from Bank of America. Please go ahead.
Hi. This is Chi on for Jason. Thanks for taking our question. I guess my question's 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? I guess for either Dr. Khella and the company as well, do you think there's gonna be any safety or monitoring requirement similar to TEGSEDI? Or do you think the label is gonna be closer to vutrisiran with five and A being the only notable warning on the label? Thank you.
Well, I'm happy to take the second part of the question. We don't expect any unusual monitoring in the label for eplontersen, period. The drug has shown remarkable safety across both the NEURO-TTRansform, the Cardio-TTRansform study, the phase one study. There's no evidence of any of the baggage that has been linked to inotersen, an earlier generation molecule.
That has dosed at 20 to 30-fold higher doses compared to eplerenone. We don't expect anything unusual in the label with respect to monitoring period. What was the first part of your question, which I think you directed it to Dr. Khella?
Yeah, I was just wondering, if the doctor's view on the overall efficacy and safety profile of eplerenone relative to RNAi-targeted products. I'm wondering if they, the doctors see it as similar or is there anything that is uniquely different between eplerenone and RNAi-targeted therapy that you would like to highlight?
No, I mean, you know, you saw the safety data that was presented. It was great. It looks like a very well-tolerated drug without any real safety concerns. I don't have any concerns about it.
The efficacy?
Well, the efficacy, you know, speaks for itself. We've you know, the study has shown that the drug is very effective in. When you look at the patients who have amyloidosis, it's a relentlessly progressive disease, and it's a systemic disease. you know, 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, you know, in just the mNIS+7. my deduction is that this drug improves systemic well-being in addition to just the neuropathy.
Thanks, Sami. Next question.
Next question comes from Kostas Biliouris from BMO. Please go ahead.
Hello, everyone. Thanks for taking my questions. 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. The second one is whether the difference between the reduction in TTR from eplerenone and other drugs in the space is meaningful in your view or is not that important. Thank you, and sorry if I missed this point, but my line was dropped a couple of times.
No problem. Thanks, Kostas. I could turn it over to Eugene to address the clinical question, but I, there's not much to say. We look forward to doing a deep dive into the data more, and we'll look at individual patients. We'll do everything we can just to learn more about the science behind TTR amyloidosis and the pharmacology of eplerenone. We'll look at the relationship between TTR lowering on an individual patient and clinical response. We will look at the same for individual basis, the correlation between mNIS+7 and Neuro-QoL 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, you know, 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 if once you get to a certain point, you know, 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 eplerenone and TTR amyloidosis. We don't have that data now. That'll be coming. Finally, TTR reduction is very important. It's very important. It is the root cause to be able to show and to speak to in your label.
We showed a mean reduction of 82% plus reduction of TTR in this study. That is very competitive. It's important to have that in our label because we all know that TTR is the root cause of this disease. It'll be very important to be able to, you know, 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. Please go ahead.
Hi. Thank you so much for squeezing me in, and 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, you know, when you're thinking about might be the right time to make that decision. Thank you.
Sam, would you like to?
Yeah. You know, the study as designed right now goes up to a maximum 140 weeks. We built into our statistical analysis plan some possibilities for earlier looks. Certainly blinded event rates will be one, but also looking at, you know, the other trials that are going to be reading out and looking at their event rates. That's also part of it. The bottom line is, you know, 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. You know, when we upsized enrollment last year, we had several objectives to accomplish. One was to ensure that we had the right powering for a for this, for the patient demographics that exists today for TTR cardiomyopathy, a demographics that is very different than the tafamidis ATTR-ACT study. Patients are milder, 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 use in that study and naive patients in that study. We can make claims when the 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. I am, and, you know, as I said, a good balance between tafamidis usage and 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 this study. All three of those objectives are well in sight, and we think that we're gonna have them well accomplished when we complete enrollment soon. Thanks, Will.
Thank you.
The next question comes from Yaron Werber from Cowen. Please go ahead.
Hi, this is Brendan on for Yaron. Thanks for taking the questions, guys. Just a couple 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 plan to, that you think would be especially attractive that you could target in the initial PM launch but maybe set you up for success later on? Just trying to get a kind of a feel on how that strategy plays into effect here. Then also, just really quickly, do you see any option or have any intention, either through the 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 kinda stick to the strict monthly dosing regimen? Thanks very much.
Yeah, I'll definitely take the first part of the question. You know, 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, but do they care enough to treat about it? We can do that with a little bit with our AI tools. We just went through kind of the tools that A-AZ has already developed. 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.
Yes, we will be there, you know, as we get more and more into the polyneuropathy launch leading to the cardiomyopathy, given how Dr. Khella describes 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. It's a really big part of our approach.
Yeah, to address the second part of the question, do we have the option to look at less frequent dosing? First, I want to highlight what Dr. Khella said is he doesn't see an advantage between, you know, monthly versus 3 months for this severe terrible disease, especially. Then Onaiza's comments earlier that an at-home self-administered autoinjector is a big advantage for these patients, as Dr. Khella also highlighted. 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.
What I'd also add that we have, to address your question, is we have a lifecycle 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. That is the last question for today's webcast. You know, 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 for the, 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 is a turning point for SOD1 ALS patients, their families, and caregivers, and has the potential to transform the way future ALS drugs are developed. Importantly, QALSODY follows 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. For now, that's all we have. Thanks again for joining us for today's call, and have a great afternoon.
Conference is now concluded. Thank you for attending today's presentation. You may now disconnect.