Arrowhead Research Corporation Morgan Stanley 24th Annual Global Healthcare Conference

Sure. Thanks again for having us here. It's really a pleasure to join you today. Okay. The ARO-DIMER-PA, I think, was a breakthrough for us and I think for the field, for a couple reasons. One, broadly this is the first time anybody has shown knockdown of two genes with a single molecule using RNAi. I think that that is an extraordinarily powerful approach that could be used across indications. I think that's important as a proof of concept that we can do this. We have several additional dimmers that we are developing as we speak, and you'll probably see those enter the clinic, or see some of them enter the clinic, next year in 2027.

Now more specifically, we're excited about the candidate, because it could be a quote unquote "complete way to treat mixed hyperlipidemia patients." These are about 20 million people in the U.S. who have elevated LDL and elevated triglycerides. These folks can be treated today with PCSK9 inhibitors to lower the LDL portion, but there's nothing to completely treat them. Our goal here was to be in the ballpark, was to lead to a reduction in LDL that is somewhere similar to current PCSK9 inhibitors. Then on top of that, lower triglycerides as well, that is somewhere similar to what we're doing in plozasiran as a pancreatitis drug. I think we hit those in spades.

We are seeing at least as good LDL reduction in this population as folks have seen with PCSK9s writ large, and we are seeing similar TG reductions that we saw with plozasiran. We go forward with something that we think is really compelling. James, you want to talk a bit more about the granular data?

Sure. Yeah. I think one of the things to emphasize in the data we released this morning was the ApoB reduction, fairly large ApoB reduction of about 50%. That is a little bit better than what some of the PCSK9 inhibitors have shown in a similar mixed hyperlipidemia population, and that's likely attributed to what we showed was the PCSK9 effect, but the additional effect of ApoC-III knockdown on ApoB. I think this is evidence that you're hitting all of those atherogenic lipoproteins from two different pathways, the PCSK9 pathway and the ApoC-III pathway. The data today were just single-dose data. The study is fully enrolled, so we should have multi-dose data at a medical conference down the road.

Yep. Go ahead. Yeah. I was going to say, of course, you never know how good a drug is until later in development, of course.

But what we have here, I think, is a really unique situation that at this very early stage, early in a phase I study, it appears that we have a drug. We know how our drugs interact with people from a safety standpoint. We've been in thousands and thousands of patients with our GalNAc constructs, so we feel pretty good about where the safety should go. We know how ApoC-III inhibition affects people with plozasiran now in many, many patients. The keys here are PCSK9 reduction and LDL reduction on the one side, and ApoC-III reduction and triglyceride reduction on the other side. We're seeing just blanket consistent good results there.

It certainly feels like we have something that could be extraordinarily powerful for this population. Now we just need time. Our hope here is that we can have this dual regulatory pathway where we can run two pivotal programs. One is based solely on LDL reduction as a primary endpoint. All the PCSK9s were first approved based solely on LDL reductions. That is a year-long study. By doing that, we think we can get to market fairly quickly, and start to penetrate this market while we are doing a cardiovascular outcomes trial. If you look at inclisiran, that has a run rate of around $2 billion right now, and they have not had outcomes data readout yet. I think that you can address a sizable part of this market fairly quickly based solely on the biomarkers.

Sure. Yeah. The single-dose cohorts enroll sequentially, and what that means is that we have different lengths of follow-up right now at each dose level based on the duration we have seen for the majority of the dose levels. We just do not have duration for the top dose level yet. I think we are looking at quarterly at the most frequent. We will see if we can push that to every six months as the data come in, but I feel confident around quarterly dosing.

Yep. We will talk more about that when we present the data at a medical conference down the road, maybe Q4.

There's a baby step before the pivotal.