Arrowhead Research Corporation Status update

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. Just before we start, I just want to make sure everybody knows we will be making forward-looking statements today, so refer to all the risk factors in our SEC filings. Here is the flow of the day. I am going to give a quick introduction. Our CEO, Chris Anzalone, will talk about how this 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 and Chief Medical Officer, will talk about the development of the new TRiM CNS subQ delivery platform on how it applies to ARO-MAPT and some of our initial preclinical results with the platform, as well as with ARO-MAPT. Then he will move on to the interim clinical results from the phase I/II study. Then Chris will come back and talk about some key takeaways, and then we will have time for a handful of questions from the panel after that. Before we start, I just want to introduce Dr. Boxer. He is a Professor of Neurology at UCSF. He is the endowed professor in memory and aging, and importantly, he runs their clinical trials research unit for both Alzheimer's as well as frontotemporal dementia, which is one of those primary tauopathies that we will talk about. We are very fortunate to have him today.

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 will 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 believed 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's 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 term holy grail is overused, but I do believe that delivering oligonucleotides via subcutaneous administration to the brain is a therapeutic holy grail. Second, broad distribution within the brain is critical for treating many indications, and animal studies across rodent and non-human primate species suggest that our TRiM platform is capable of this. Third, a good durable and deep knockdown of at least 50%-60% was our goal, and the ability to detect this via the cerebral spinal fluid would be helpful. All of these were born 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 a 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 one wholly owned and one 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 three 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 is 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. 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've a protein-like tau, you can see that, for instance, in Alzheimer's disease, both the amount and the anatomical location of this insoluble protein, this 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 Braak 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.

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 get. 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. What is tau? Tau was initially thought just to be a protein that binds to structures within neurons called microtubules, and that is an important role for tau, but over the past decade or two, we've learned that tau plays many important roles in neurons in the brain.

It is in the nucleus, and can bind to nucleic acids like DNA and RNA. It seems to also play a role in energy metabolism in neurons, in the structures called the mitochondria. Tau is also found in the synapse, the structures that allow one 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 one cell or one neuron to another.

As I mentioned, the most common tauopathy, and the tauopathy that many of us are familiar with, is 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 A-beta, or the plaques that are present in many people's brains, that really drive the overproduction and spread of tau throughout the brain. In primary tauopathies like progressive supranuclear palsy, corticobasal degeneration, Pick's 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.