Arrowhead Pharmaceuticals, Inc. (ARWR) Earnings Call Transcript & Summary

Good afternoon, everyone, and welcome to the Arrowhead Pharmaceuticals [indiscernible]. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Arrowhead website following the conclusion of the event. I'd now like to turn the call over to Vince Anzalone, Senior Vice President of Finance and Investor Relations at Arrowhead Pharmaceuticals. Please go ahead, Vince.

Thank you, Tara, and thanks, everybody, for joining us today to discuss the ARO-MAPT interim results from the Phase I/II study and the first results with our new TRiM delivery system for CNS, really excited about these data. So just before we start, I just want to make sure everybody knows, we will be making forward-looking statements today, so I refer to all the risk factors in our SEC filings. And here's the flow of the day. I'm going to give a quick introduction, our CEO, Chris Anzalone, talk about how this kind of ushers in a new era for RNAi therapeutics in the brain. Dr. Adam Boxer from UCSF will talk about the role of tau in Alzheimer's disease and other primary tauopathies. James Hamilton, Arrowhead's Head of R&D Chief Medical Officer, who'll talk about the development of the new TRiM CNS subcu delivery platform and how it applies to ARO-MAPT and some of our our initial preclinical results with the platform as well as with ARO-MAPT and then he'll move on to the interim clinical results from the Phase I/II study. And then Chris will come back and talk about some key takeaways and then we'll have time for a handful of questions from the panel after that. So before we start, I just want to introduce Dr. Boxer. He's a Professor of Neurology at UCSF. He's the endowed Professor in memory and aging. And importantly, he runs their clinical trials research unit for both Alzheimer's as well as front to temporal dementia, which is 1 of those primary tauopathies that we'll talk about. We're very fortunate to have him today. And please, by all means, ask any questions you want because he knows all the answers. So thank you, Dr. Boxer for joining us. Now I'll turn the call over to Chris.

Thanks, Vince. Back in 2009, we decided to focus Arrowhead on RNAi. The field was in its infancy, but we believed that if we could develop the base technology and overcome delivery challenges, RNAi could be a truly revolutionary modality. We also believe that part of its power was in its potential breadth. So we sought to bring it to wherever disease is. As such, our early focus was to create a set of platforms capable of safely and efficiently bringing RNAi to different organ systems and cell types. Today is not the culmination of this drive, we are always building -- always expanding but it is a significant milestone, an important day. Next slide. Today, we present Arrowhead first clinical proof of concept for ARO-MAPT and importantly, our expanded TRiM platform for CNS delivery. There are several important points going into this early data release. First, the TRiM holy grail is overused, but I do believe that delivery in oligonucleotides via subcutaneous administration to the brain is a therapeutic holy grail. Second, broad distribution within the brain is critical for treating many indications in animal studies across rodent and nonhuman primate species suggest that our TRiM platform is capable of this. Third, good durable knockdown a good durable and deep knockdown of at least 50% to 60% was our goal and the ability to detect this via the cerebrospinal fluid would be helpful. All of these were borne out in animal studies. Fourth, we think the combination of employing RNAi in the brain with simple subcutaneous administration, potentially at home, that provide deep knockdown across brain regions, lasting several months between injections likely opens the possibility of treating many conditions from neurodegenerative to psychiatric to obesity. This feels like the company's worth set of potential value unto itself. Next slide. Today's data have near-term importance beyond ARO-MAPT. As shown here, we currently have 1 wholly owned and 1 partnered candidate in the clinic using the TRiM CNS platform, and we expect to add another partnered candidate in the clinic in 2027. In addition, we plan to introduce at least 3 new wholly-owned CNS candidates to the clinic over the next 12 months alone. I expect CNS candidates to be an increasingly important part of our pipeline in the near to midterm. But let's also be clear, today is about ARO-MAPT and the important data we have generated thus far. We will show deep and durable knockdown in the CSF, and this is only after loading doses. We may see another step down in both knockdown and durability in the multiple dose cohorts as those data become available. Given our animal data, we have a high degree of confidence that knockdown is occurring consistently across brain regions. As you will hear, there are substantial evidence that tau reduction may be important for treating Alzheimer's disease, and we think it is clearly important in primary tauopathies. Next slide. Dr. Boxer?

Good morning, everyone. Happy to present to you today and tell you a bit about the role of tau in Alzheimer's disease and other tauopathies. So the objectives are to review the current treatment landscape in Alzheimer's disease, understand the implications of recent therapeutic advances in amyloid and tau therapies, evaluate the rationale for tau-targeting therapies. I want to frame some of the key consideration for the next-generation therapies and talk about tau reduction for the treatment of primary tauopathies, which seems like a very exciting possibility. Some people may be familiar with the history of research in Alzheimer's disease and other neurodegenerative diseases of aging. But in general, in the diseases that we call tauopathies, when we look at someone's brain after they passed away and we look at it at autopsy and we stain for protein like tau, you can see that, for instance, in Alzheimer's disease, the -- both the amount and the anatomical location of this insoluble protein, this brown -- dark brown stuff that you see, is strongly correlated with the severity of symptoms and the types of symptoms that the patient experienced during life. This is true not just for Alzheimer's disease. And again, in the upper left-hand corner, these are the famous rock stages of Alzheimer's disease that we use neuropathologically to stage Alzheimer's disease, but they're also recapitulated now with tau sensitive pet ligands, but it's also true in other tauopathies that we call primary tauopathies like progressive supranuclear palsy Richardson syndrome on the bottom left. And on the right, chronic traumatic encephalopathy, the disease that many football players and others who have had repetitive brain injuries guests. And so it stands to reason that if the amount and the anatomical location of this insoluble tau is strongly correlated with the symptoms during life then one treatment approach might be to try and either reduce this tau in the brain or prevent its buildup in the first place. So what is tau? Tau was initially thought just to be a protein that binds to structures within neurons called microtubules and it is. That is an important role for tau, but over the past decade or 2, we've learned that tau plays many important roles in neurons in the brain. It is in the nucleus and combined to nucleic assets like DNA and RNA. It seems to also play a role in energy metabolism in neurons in the structures called the mitochondria. And tau is also found in the synapse, these structures that allow 1 neuron to communicate with another. And it seems to play a role in the synaptic transmission or the communication that's mediated by neurotransmitter release from 1 cell or 1 neuron to another. As I mentioned, the most common tauopathy and the tauopathy that many of us are familiar with a Alzheimer's disease, but we consider that to be a secondary tauopathy. And that is because, although tau may be present in many people's brains due to normal aging, prior to the buildup of amyloid, we think that it's beta amyloid or the plaques that are present in many people's brains that really drives the overproduction and spread of tau throughout the brain. In primary tauopathies, like progressive supranuclear palsy, corticobasal degeneration, PICs disease and individuals with tau mutations, we think it's the tau itself that's really doing all the damage on its own. And we don't know as far as what's maybe promoting its spread throughout the brain. There's also quite a bit of evidence from genetic studies like genome-wide association studies that even though we often don't find insoluble tau at autopsy in the brains of patients with other diseases like Parkinson's disease, multisystem atrophy or epilepsy that from genetics, we know that tau is also very strongly linked to the risk and sometimes the progression of these diseases. We think that in all of these diseases, a central pathogenic mechanism is the accumulation of this toxic misfolded form of tau and we call that toxic gain of function. There's quite a bit of evidence that this toxic misfolded brown stuff that I showed you on the previous slide may be spreading from 1 cell to the other throughout the brain and this causes neuronal and glial dysfunction and eventually synaptic loss and degeneration. And as I'll mention in a moment, there are certain cells, including neurons, have evolved mechanisms to resist the spread and the build above this toxic gain of function, but we think, in disease, this overwhelms the compensatory mechanisms. We think that also aging may be a part of this problem. So in Alzheimer's disease, we have a big advantage in studying the progression of the disease. Many people may be familiar with these biomarker graphs, some people call them Jack curves. Up in the top right-hand corner, you see a picture or a schematic of the tau protein. We know that the tau protein is usually cleaved into 2 pieces, and the end terminal fragments are soluble and float around. And what you can see is that in most people who go on to get clinical Alzheimer's disease, there's evidence from these biomarkers that we can measure -- in living humans we can measure soluble forms of beta amyloid or amyloid plaques using PET that the soluble form of tau builds up in parallel with the amyloid plaques, which are often present for decades in individual brains before they develop symptoms of Alzheimer's disease. In Alzheimer's disease, we can also measure that insoluble tau that I showed you on the first slide using PET. And it's that second half on the right of the tau molecule that includes the microtubule binding region that seems to be accumulating. And you can see there's sort of a point of inflection that occurs right before the onset of symptoms in most people who get Alzheimer's disease. We call that the catastrophe of Alzheimer's disease. Actually, it's Resa Sperling and Keith Johnson, who coined that turn. But the important point is that patients can have amyloid plaques in their brains for decades without any symptoms, but when that insoluble form of tau starts to accumulate and the catastrophe occurs, that's when people develop symptoms. And so the goal is to try and prevent the catastrophe or at least to reduce it or blend it. We know now that there are -- and we -- clinicians are very excited that there are 2 FDA-approved anti-amyloid drugs that are commonly used now in the United States to treat Alzheimer's disease. These are data from the Phase III trial of 1 of these drugs called [indiscernible]. What you can see in the left most panel is that using a common global measure called the clinical dementia rating scale, some of boxes, that treatment with donanemab in people who are already symptomatic with Alzheimer's disease who have prodromal to mild disease, leads to a modest but significant reduction in the rate of decline by about 35% to 40%. And in parallel, you can see that the number of amyloid plaques is really profoundly reduced by the drug. So reducing amyloid is associated with this benefit in symptomatic Alzheimer's disease, but it's a relatively modest benefit, and it may not be enough. As I told you previously, there's been a long-standing hypothesis that it's really the tau that's the problem and that it's the amyloid that's driving the tau and the catastrophe. And so what we think is going on with anti-amyloid drugs is that you see in that dark red curve is that we can dramatically reduce the amount of amyloid plaques in the brain with either donanemab or lecanemab. But when we start at least in patients who are very mildly symptomatic already, the catastrophe is already well underway in that dark blue line. And what we know from Talpa is this has very modest effects on blending or reducing the catastrophe, and this leads to a modest effect on reduced cognitive decline. We think that a drug that could really effectively blunt the catastrophe, maybe by targeting tau itself, would have a much larger effect. And that's the hypothesis and that we're hoping to learn more about in future trials of tau therapies. Where did the idea of tau therapies come from? Well, people have been working on this for over 20 years. Some of the first experiments were done by Leonard Nike and Eric Roberson at UCSF and the Gladstone Institute. And they showed that in Alzheimer's disease, transgenic mice who carry a human Alzheimer's peaker [indiscernible] protein transgene, that about a 15% die after about 6 months, but reducing the endogenous amount of tau by genetically knocking out 1 of the mouse tau alleles makes these mice resistant to human amyloid toxicity, not only that but in a different line of mice reducing the tau even by just 1 allele or 50% makes them resistant to tonic-clonic seizures from a toxin called [indiscernible]. And so again, this supports the idea that tau is important for maybe Alzheimer's disease, but also many other brain diseases. And so an effective tau drug might find a role in treating many neurological and neurodegenerative diseases. So fast forward now over 2 decades, and we now know from Biogen's experience with derinursin, this is our data from the Phase I study. This is an intrathecally administered tau antisense that in patients with mild to moderate symptomatic Alzheimer's disease, that reduction of tau by up to about 60% measured in the CSF using CSF phospho-related tau assay is safe and well tolerated. And remarkably, in these Phase I results, we saw that for the first time, not only is it possible to stabilize the further accumulation or to maybe blunt that catastrophe as measured by tau PET in a small number of people who were followed for 2 years, but there appeared to be less of that red stuff in the lower right-hand panel, which is the insoluble tau. So not only can a genetically targeted tau therapy seem to reduce the further accumulation of tau, it seems partially reversible. And this was a really big deal for our field. Many people are really excited because up until this point, we thought that accumulation of tau was an irreversible process. Now we think that may not be true. And so I think as many people know, there has been a larger Phase II trial of the same antisensoligo nucleotide, derinersen. I'll show you the key results in just a moment, but the trial was overall negative, and we'll discuss why. But this drug is now -- has been announced to be moving to Phase III, underscoring the promise of this approach for treating Alzheimer's disease. So I'd like to just take a step back now and remind you a bit about the genetics and the biology of tau because it's really important that you understand this for understanding the different diseases that we might wish to treat with a genetically targeted tau drug. So this shows that tows an alternatively spliced gene that gives rise to 6 protein isoforms in humans, and their name for the number of microtubular mining domains, either 3 are 3 microtubular binding repeat tau or 4 microtubulbinding repeat tau. And in a normal adult grain or in someone with Alzheimer's disease, the ratio of these protein Alzheimer's -- protein isoforms excuse me, is equal, but in the primary tauopathies, we see in these sporadic diseases like corticobasal degeneration and PSP, there seems to be far too much for repeat tau and in a different tauopathy called PIC disease, which causes frontotemporal dementia, there's too much to repeat tau. So it seems that having too much or an imbalance of isoforms may be toxic to neurons. It turns out also that there are rare families around the world who have autosomal dominant mutations in the tau gene itself and these give rise to severe early onset forms of dementia or movement disorders. And remarkably, where that mutation is in the tau gene has a big effect on how the mutation exerts its effect biologically and also on the phenotype or the symptoms produced by that mutation. So for example, mutations in INTRON10 lead to too much production of for repeat tau, and the individuals who have those mutations often develop clinical symptoms that look like CBD or PSP. Conversely, when we do a genome-wide association study of the sporadic or the non-genetically determined diseases, CBD and PSP, we find the strongest genetic risk factor are single nucleotide polymorphisms or sequences in or around the tau gene itself with 1 particular sequence called H1C, probably increasing the amount of tau expression and greatly increasing risk for these diseases. And we now know that there are other genes that have been identified that may help to reduce the amount of tau expression or improve its clearance by the cells that are protective against these diseases. So why am I mentioning this? Well, it's important as we think about the possible indications for tau-targeted drugs that in those who've studied the drug development in general, the odds of bringing a drug successfully to market is much higher if there's a strong genetic link between the target of the drug and the disease itself. And what I've mentioned is that in the -- with tau, there are very strong links to primary tauopathies, but less so for Alzheimer's disease. And in fact, most of the mouse models that have been used to develop tau-targeting drugs are made with these mutations, P301L and P301S that cause human early onset, front other dementia. And so there -- we've already seen promising clinical data from dirinursen in patients with Alzheimer's disease, but what I want to make the case for is that there may be even a stronger rationale from a genetic perspective to treat primary tauopathies with tau-targeting drugs. So what's going on with Alzheimer's disease? If there's no genetic link, why do we think that we should be treating these patients? Well, with the tauopathy, well, you already saw their relationship temporary at neuropathologically between tau in Alzheimer's disease. And a recent study from Judit Steam at Boston Children's that we helped with showed that although genetically, there's not much of a link between tau and Alzheimer's disease, at autopsy, when you quantify the amount of insoluble tau in that rightmost column in the brain when someone passes away, there's about 50-fold higher levels of insoluble tau, that brown stuff I showed you in the dark in the first slide, than there is in the primary tauopathies or in control. So Alzheimer's disease is really a disease of tau, too much tau, but it may be building up for other reasons. So what have we said? Well, we think that the central hypothesis of Alzheimer's disease is that tau is really leading to the clinical symptoms of disease. This is promoted by having amyloid plaques in the brain for decades. But there was a worry and before we talk about the Phase II results with [indiscernible] that most of these hypotheses were based on observational or correlative data and maybe the tow that we measure in living humans or people who come to autopsy assisted marker of some other pathogenic process. So the alternative hypothesis is that tau increases with these diseases, but something else is really leading to the clinical symptoms. And that's why the Phase II [indiscernible] trial was so important for the field. Again, I told you that in PSP and primary tauopathies, we think that that's really to was the only pathogenic protein that's present in most cases. And so we have much greater confidence based on that and the genetic link that it's the tau that's the real problem. And of course, in tau mutation carriers, we know 100% for certain that it's the tale that's causing the disease. So again, many have seen these results. These are from the Biogen deranursen trial. And remarkably for the field, what was shown is that reducing tau by 60% roughly in the CSF in patients with mild prodromal to mild Alzheimer's disease was also associated with a 40% or 42% slowing of cognitive decline at the optimal dose, which turned out to be the lowest and not the highest dose of drug. This is really remarkable because it helps to support this hypothesis that tau is a central pathogenic protein in Alzheimer's disease because all of these patients still had high levels of amyloid in their brain, but reducing tau was associated with the clinical benefit. Unfortunately, this trial did not produce the results we had all hoped for, which was across the board benefits, and so there was less of an effect seen on activities of daily living or on global measures like the clinical dementia rating scale that I showed you in the slide with donanemab earlier. And so the question is, why wasn't there a bigger clinical effect of reduction of tau? Why was it only 42%? And why was it only at the lowest dose? Well, one thing that was reported in these results at AAIC was that there were dose-related side effects, either confusion and falls, most commonly in the 1 week following injection. And maybe these mitigated some of the benefits of lowering tau in these patients. And you can see in the lower right-hand corner in the subset of people who received longitudinal to taupath that in orange, this was the optimal dose, and this had the least amount of insoluble tau reduction, but there was insoluble tau reduction. So 1 question that we're all struggling with in the field right now is, is there something -- was there something about dirinersen because it's an intrathecally administered ASO that is leading to the side effects that cause confusion and falls and maybe it's inflammation, maybe this was mitigating the benefit of reducing tau. Alternatively, and we hope this is not the case, but we don't know for sure, maybe there was some on-target toxicity of tau reduction. And even though reducing tau in animals has been benign and genetic studies of humans suggests that loss of tau function is not associated with disease that may be what this study is telling us is that maybe there is a limit to what we can do. But I think we just can't resolve these based on these data. Other possible reasons why more prominent clinical benefits were not observed in the study, well, maybe they started too late disease, maybe you have to start earlier in a catastrophe or maybe you need to remove both a beta, and I mentioned that the a beta was still present in these patients and too and also maybe in the future other pathogenic proteins like alpha-synuclein, about 30% of these individuals are -- were also found to be alpha-synuclein positive. And in another study funded by the U.S. National Institutes of Health, we are doing a platform trial where we're combining amyloid and tau therapies. I'm not here to tell you about that, but combination therapy may be something that we will do in the future to really see the greatest benefits. And of course, as I suggested to earlier, maybe primary tauopathies will respond better. This is an important insight that we've had from new technology called cryoelectron microscopy. And really, it turns out that using this technology, we've been able to solve the 3-dimensional structure of the aggregates and the various primary and secondary tauopathies. What we've learned is that it's that the core structure which corresponds to the micro-tubal domain has a very regular, what we call amyloid structure in each of the tauopathies. And that in different tauopathies remarkably, the 3-dimensional structure of this core is different. So maybe it's actually the core that's driving the disease or the actual structure of these aggregates. We don't know for sure, but what we do know is that there are other -- many other therapeutic approaches to tau, many of them are immunotherapies and the first 5 or so failed. And we think that the reason why they failed is because instead of targeting the tau core structure, they targeted the end terminal regions of tau, which I told you earlier, often cleaved off. Some of the newer immunotherapies target this core structure and are beginning to produce more promising results. And so there may be other approaches to tau therapies particularly immunotherapies that target this toxic core structure that might also eventually find their way to the clinic. One example or the first example that's been tested in a large Phase II is [indiscernible]. And in a post tech study in individuals who either had low tau at baseline or ApoE4 noncarriers in the upper left-hand panel -- or excuse me, in the middle left-hand panel, you can see that this antibody that reduced extracellular tau by binding to the end terminal portion of the microtubule binding region, seem to attenuate tau PET uptake and also slow decline on the ADAS COG. And this, again, was -- these data were presented a few years ago, but this was very important for the field because it was the first experimental demonstration with an interventional study in living humans that neutralizing extracellular tau with a monoclonal antibody had a clinical benefit or potential clinical benefit. And this really supported the hypothesis that tau spreads from 1 cell to another through the extracellular space. So these are, I think, promising developments for tau therapeutics. What about primary tauopathies? Well, remarkably, we've been doing clinical trials in progressive supranuclear palsy for over 20 years. But for the first time, earlier this year, presented at ADPD a trial with a different antisense oligonucleotide called NEO752, showed that in patients with PSP Richardson syndrome, reduction of tau in the CSF by about 25% to 30% was associated with the stabilization of neurodegeneration as measured by CSF neurofilament levels. Neurofilament is an axonal protein that's released when neuro degenerate. This was really remarkable because never before in a clinical trial in PSP had we've ever seen anything that seem to have an effect on neurodegeneration or disease modification. And so this drug is now in a Phase III study. So to summarize, what I've told you is that hardening tau really reflects the close clinical pathological correlation between insoluble tau cumulation and many different neurodegenerative diseases of aging, not just Alzheimer's disease, reducing production and targeting all forms of tau, maybe a pragmatic solution, you've seen the challenges wit immunotherapies. there are exciting results with both [indiscernible] and NEO752 to other genetically targeted tau therapies, and we're eagerly awaiting the next round of results with these drugs. And there is a huge global unmet need for both Alzheimer disease, but for primary tauopathies in particular, because these are severe diseases with no approved therapies that can help these patients. We think or I think that there is a very strong rationale for testing tauopathies outside of Alzheimer's disease, and I told you that there are very strong genetic link suggesting maybe even these drugs might even potentially work better for primary tauopathies. So with that, I'm going to end, and I'm sure there will be time for questions, and I'll turn this over to James. Thank you.

Thank you, Adam, for that great overview. So now we'll switch gears and talk about platform and the ARO-MAPT study. So for those of you who are new to the story, Arrowhead remains focused exclusively on developing siRNA therapeutics. We leverage the TRiM platform, which is a set of rules and algorithms for sequence selection coupled with a library of linkers and targeting ligands to facilitate siRNA delivery into multiple cell types. Any given platform is modular, which allows for a degree of repeatability in GLP toxicology studies and drug manufacturing. Broadly, the TRiM discovery platform is designed to facilitate rapid progression from concept to clinic. The CNS platform uses a TFR1 targeted fab covalently linked to the siRNA payload to facilitate subcutaneous administration and effective delivery of siRNA across the blood-brain barrier. This strategy has several advantages over the intrathecal route of administration, which will be described in the next few slides. Here in monkey studies, we've confirmed the ability of the platform to silence MAPT expression by better than 75% across various brain regions with subcutaneous administration of development candidate, ARO-MAPT. This includes effective silencing in Alzheimer's disease relevant brain regions, including the hippocampus. In a long-term multi-dose monkey study, we confirmed the ability to maintain MAPT silencing after repeated doses. These data support long duration of effect with up to 60% CSO tau knockdown up to 4 months after the last dose. Importantly, the knockdown achieved with subcutaneous administration of siRNA delivered across the blood-brain barrier using the Arrowhead CNS platform is more consistent and more homogeneous as shown on the right, compared with intrathecal delivery of siRNA targeting MAPT as shown on the left. This is important because better distribution avoids concentration of drug in the spinal cord as is common with IT delivery and facilitates potentially better gene target silencing in the most relevant brain regions. Here again, we emphasize the more homogeneous drug concentrations achieved across various disease relevant brain regions with subcutaneous administration using the Arrowhead platform as shown in monkeys on the left. This is compared to the highly heterogeneous delivery seen with IT administration and IT-administered ASO in a clinical radiotracer study as shown on the right. Note the lack of signal in the brain in some participants in the panel on the right and the strong signals seen in the lumbar spinal cord. So now that we've reviewed the platform, let's switch to the ARO-MAPT clinical study. ARO-MAPT SC1001 is a dose-escalating study of ARO-MAPT in healthy volunteers and in patients with early Alzheimer's patients. The study is intended to understand safety, PK and pharmacodynamic response in healthy volunteers and in Alzheimer's patients using multiple escalating dose levels and various dose interval strategies. The Alzheimer's patient cohorts will enroll individuals 50 to 80 years of age with early Alzheimer's based on CDR and MMSE score cutoffs as well as the presence of at least 1 biomarker consistent with Alzheimer's. Participants must not be on or have no plans to initiate Alzheimer's disease-modifying therapies, including anti-amyloid therapy for the duration of the study. The study has or will have sites open in Canada, U.K., Australia and New Zealand, and the healthy volunteer enrollment is complete. We're currently focused on enrolling the Alzheimer's patient cohorts. Primary endpoint of the study is safety, but we have multiple pharmacodynamic endpoints built into both the healthy volunteer and the Alzheimer's disease patient components of the study, and we will be evaluating various cognitive rating scales in patients. However, today, we'll be focusing on the data that's available from the healthy volunteer single escalating dose cohorts. Briefly, here, we show baseline characteristics, generally consistent with those of a typical healthy volunteer population. And here, we show CSF total tau reduction over time by dose group. After the initial loading dose, we're seeing mean CSF tau reductions of up to 73% and a maximum individual reduction of up to 85% with evidence of dose response and with no reductions in the placebo group. On the next slide, we show individual CSF tau responses, indicating a generally consistent post-dose magnitude of tau reduction across individuals receiving ARO-MAPT compared with no response in placebo. Available safety data so far is supportive of continued dose administration and a progression to later-stage studies. ARO-MAPT has been well tolerated with no reported serious treatment-emergent AEs, no neurobehavioral AEs such as confusion, and no persistent anemia. In terms of next steps, we plan to first finish dosing in the multiple ascending dose cohorts in healthy volunteers with a planned data update next year. We also plan to continue enrollment in the Alzheimer's patient cohorts also with a planned data update in 2027, and we have initiated discussions with regulators in anticipation of later-stage studies in MAPT variant frontotemporal dementia and progressive super nuclear palsy. In conclusion, Arrowhead's subcutaneous CNS siRNA delivery platform has been well tolerated to date in healthy volunteers in Alzheimer's patients. Subcutaneous administration of ARO-MAPT in healthy volunteers has demonstrated deep dose-dependent and durable knockdown of CSF total tau with potential for more homogeneous brand distribution. These data represent initial clinical validation of ARO-MAPT and importantly, of the TRiM CNS platform, which is an important milestone for Arrowhead and also for our partners using this platform. In addition to ARO-MAPT, Arrowhead has multiple wholly owned CNS targeted preclinical development programs, including 2 planned for CTAs by end of 2026 or early 2027. And I'll now hand the call back over to our President and CEO, Chris Anzalone. Chris?

Thanks, James. Next slide. We believe that what we have shown today represents scientific and potential therapeutic breakthroughs. And this is just the first step. It appears that we are able to deliver siRNA to the CNS across the blood-brain barrier in a well-tolerated manner. Administration is by simple subcutaneous injection that could potentially be done at home as infrequently as quarterly. We see deep and durable knockdown that we expect is occurring across brain regions, including the deep brain. We could see even deeper and more durable knockdown after multiple doses. Our nonclinical work in the CNS and extensive clinical and nonclinical work in other cell types have suggested that once we validate our ability to deliver to a particular cell type, we can reliably reproduce that against other targets. Simply put, it appears that cells don't care what siRNA sequence we use. So this early clinical proof of concept could have a wide-ranging predictive value across any number of disease treatments. With a minimally invasive platform that enables us to silence virtually any gene expression in the brain, including in both neurons and neuroglia, we should be able to address conditions from neurodegenerative to psychiatric [indiscernible] disorders to migraines, to obesity and others. It is difficult to overstate the flexibility and importance of this platform, we believe we are limited only by the number of targets we can identify. [indiscernible] also focused on the leap forward we see in the current candidate ARO-MAPT. The biology around primary tauopathies is fairly clear and ARO-MAPT could be a powerful therapy for many of these patients. The regulatory pathway could also be fairly straightforward and relatively short, so we hope to bring ARO-MAPT to these patients as quickly as possible. More broadly, we hope to bring ARO-MAPT to the approximately 30 million to 40 million people worldwide suffering from Alzheimer's disease. Of course, this is a longer regulatory road and there is more biology to learn, but we look forward to our first data in patients with Alzheimer's next year. Next slide. We now have clinical proof of concept for the TRiM platform's ability to deliver to 5 different organ systems. As I mentioned earlier in the presentation today, our model is to bring RNAi to wherever disease is and the current expansion into CNS substantially increases our reach. We continue to build the platform and expect to reach a new cell type every 18 to 24 months. Next slide. In 2026 alone, Arrowhead has further solidified its position as the leading innovator in RNAi therapeutics. In less than a year, we believe we are the first to achieve clinical proof-of-concept of RNAi in the brain after subcutaneous administration, achieved clinical proof-of-concept of silencing 2 genes with a single molecule and achieve clinical proof-of-concept of RNAi targeted in adipocytes. We tend to continue this pace in 2027 and beyond. With respect to follow-up on these achievements, we expect to present additional data in healthy volunteers in Alzheimer's patients with ARO-MAPT in 2027 and introduced at least 4 additional CNS candidates into the clinic by the end of 2027, to present additional clinical data with ARO dimer PA in 2027 and introduce at least 1 new dimer to the clinic next year and to present additional clinical data for ARO-ALK7 by the end of 2026. With that, I'd now like to open the call to your questions, and thank you for your attention today.

Thanks, everybody. Let me compile some questions. We have time for 3 or 4 separate questions. Okay. First question is from Madison El-Saadi at B. Riley. It looks like the first part of this will be for Dr. Boxer and then the second part, probably for James. First part is, could the planned FTD and PSP studies reach approval faster than Alzheimer's? And what would a design look like for those types of clinical studies. So we'll start there, and then I'll get the second part after.

That's a great question. I'm not a regulatory expert, but my understanding is that these are both rare diseases or they're considered orphan diseases with severe unmet need. There are no approved therapies. And so within the United States, at least, there are mechanisms, regulatory mechanisms to encourage the development. And I think there may also be some patent exclusivity benefits as well that may allow a more rapid development and certain additional considerations for approvals. Also because these are rare disease populations, often it's not possible to do multiple different stages of development. Often, it's a Phase I and then a large Phase II/III. So we do think there are significant advantages. And then the third reason is that these diseases tend to have a much rapid -- much more rapid rate of progression, so you can do a faster, smaller, more efficient trial. And just one last plug, which is the National Institutes of Health are also supporting a platform trial for progressive supranuclear palsy, which is up and enrolling now. And we hope that drugs like this could find their way into our platform trial.

Great. And then, James, what's the time line for additional regulatory interactions? And when would we assume that we'll start FTD and PSP studies?

Yes. So we're having those discussions now. I think over the next 1 to 2 quarters should have quite a bit of a meaningful back and forth on the regulatory front with an aim of finalizing a study design. I probably don't want to give guidance on timing to start those studies until we at least have the study design pinned down, but we'd be aiming to start something in '27.

Next question is from Jason Gerberry at Bank of America. And I would also think this is probably Dr. Boxer. Which downstream measures would you expect to change if MAPT silencing is disease modifying? For example, a tau PET neurofilament light, MRI measures, synaptic measures, neuro inflammation markers or another end point? And over what observation period could these changes reasonably become detectable? And I would split split into Alzheimer's as well as primary tauopathies.

Okay. Well, there's a lot to discuss. We can spend a few more hours answering that question. But as I mentioned in Alzheimer's disease, we have the advantage that we can measure tau PET and soluble forms of tau pretty easily even in blood. And that would be the first thing that we'd look at. For -- and then again, they're well-established clinical and other biomarker endpoints in Alzheimer's disease. For primary tauopathies, unfortunately, we don't have as good biomarkers of tau. We can measure for target engagement in CSF tau levels and [indiscernible] tau levels. We don't yet have as good tau PET ligands. But as I already showed you, neurofilament light chain because these are more aggressive diseases, tends to be more elevated in primary tauopathies like PSP and tau mutation carriers, also MRI may be a good endpoint. And increasingly now coming out of proteomic studies there is very clear evidence that there're other fluid biomarkers like biomarkers of synaptic connectivity, one is is called the synaptic protein ratio that may be particularly sensitive to these effects. We would hope -- again, these are, unfortunately, for the patients, more aggressive diseases. So for PSP, a typical study is 1 year, depending on when we would start, what stage of disease. A MAPT mutation carrier trial might be a little longer 18 months to 2 years.

Thank you. Next question comes from Prakhar Agrawal at Cantor. What is the timing of Alzheimer's disease patient data? Actually, I'll head that off before James even gets to that. So in 2027 at some point, we have to see how those studies start enrolling. And then the next part of this question will probably be James and Dr. Boxer. Based on the knockdown data that you're seeing in healthy volunteers, what level of knockdown would you expect in patients? And how are you thinking about the optimal dose here? It seems like an intermediate dose of 6.4 mg per kg and 12.8 mg per kg showed mostly comparable data.

Yes. I can start on that one. I agree. I mean I think that at least after that loading dose, either day 1, 8, 15 or day 1, 15 that with those top few dose regimens, either 6.4 or the 12.8, they look very similar, right? So we may be sort of hitting the top of the dose response curve. In that case, if they all look similar, we'd probably select the lower end of that dosing range if there's no benefit to going higher. That being said, we'll have to see how things evolve after we give the the next dose, and we'll also have to see how things look in the patients. I mean Dr. Boxer can comment on this, but the kinetics of tau might be different in Alzheimer's patients. And so we'll see how knockdown looks at the various dose levels and different dosing strategies in patients compared to what we saw in healthy volunteers. I just don't know yet.