Advancing Gene Therapy for FTD with Passage Bio's Dr. Will Chou

Thank you for having me, Erin.

Sure. Sure. So, Passage Bio is developing genetic medicines for neurodegenerative disease, and as you mentioned, our lead program is in the clinic in a Phase 1/2 study for frontotemporal dementia. Now, FTD, as it's called, is the most common early-onset form of dementia, and it's a little bit different from Alzheimer's in that it's more of a behavioral dementia where patients — they do have memory loss, but they have issues with word finding, communication, and then changes in their personality. So it's a very difficult disease for patients. There are currently no therapies for FTD. And about 30% of FTD is caused by a genetic cause, and of those genetic causes, about a third of them are from what we are studying, which is FTD with the granulin mutation. And so we are looking at a very focused set of patients who have a specific mutation that causes their FTD.

Yeah, absolutely. So I would say from a scientific point of view, it piggybacks on to what I mentioned before. So first, if you talk to FTD patients and you go to the FTD patient community, the vast majority of patients with FTD do not have a genetic form. So that's one big scientific issue is that we don't have a good way of treating or even targeting the non-genetic forms of FTD. And then even within genetic FTD, there's three main mutations. There's the granulin mutation, there is the MAPT mutation, and there's the C9orf72 mutation. And the vast majority of research right now is doing what we're doing, which is going after the granulin mutation, because this is a mutation where the patients have that mutation, they're deficient in a protein, you can replace that protein and try and reverse the damage, right? So it's very straightforward gene replacement therapy. The other genetic forms of FTD, there's not as direct of a correlation between the gene deficiency and the actual pathology that delivers the FTD. So it's not as straightforward of an approach. And we know that genetic FTD patients are a little frustrated in that if you have the granulin mutation, there's four different programs that are chasing this. Other mutations, there aren't as many. And so that's a big scientific issue that we know the community is trying to address for the patients.

From a manufacturing standpoint, I'm going to keep this really simple. In our own experience with manufacturing our gene therapy, we've made fantastic progress, and so we can make this gene therapy at scale. One relatively small batch could treat over a thousand patients. So we've got the manufacturing down quite well, and it's one of the advantages of doing an AAV therapy. So we are doing AAV. It's a rather old school — I will put that in quotes — it's an older technology, but one good thing about having a technology that's been around for a while is there's a lot of experience in how to manufacture it. And so we've been very quickly able to get to a very efficient way of manufacturing this product.

From a regulatory standpoint, I will say the question that we get from most people is, what have you experienced with the new administration from a regulatory standpoint? And from our own experiences, the turnaround time has been very fast. And from what we've been hearing, both in the public and I was at the FDA a couple of months ago speaking with Dr. Makary, Dr. Prasad — they want to continue in the path that has been set before them at CBER, which was they want to give patients the opportunity to try therapies. That was very important, and Dr. Makary emphasized that he believes in both the words and the action of right to try. And so they understand that for rare diseases, which is what we are dealing with here, you're sometimes going to need alternative ways of experimenting because you don't have as many patients, and so you're going to need some creativity with your analysis plans. And we believe that this administration and this FDA is going to continue with that great flexibility and understanding that the previous administration had.

Yeah. Yeah. Great question. So we are working with a CDMO. We did all of our development in-house, so developing what the new process is going to be, but the actual process we're doing at a CDMO. We work with Catalent, and we've had great success with Catalent in making the product, both with the old method and the new method. And I think this is a big misunderstanding that is out there. We're a small biotech, we talk about larger partners, and there are some partners who are interested in gene therapies and some who are not interested in gene therapies. And one thing we hear a lot is, oh, well, there's all this manufacturing investment that needs to be made if you want to be in gene therapies. And what I would say is that's not necessarily true. There is ample supply out there right now with CDMOs for manufacturing supply. So with some of the contraction on the market, there's actually now a lot of available supply for manufacturing. And in the case of programs like ours, if you have a manufacturing process developed and it is very inexpensive to do at scale, there is no need for any company to invest in all of the in-house manufacturing. And because when you do that, you have to fill that manufacturing, right? You have to have other products that will fill that capacity, and then you have a constant pressure of, I need more and more genetic medicines. Well, you don't necessarily need to have that model. I think the CDMO model is absolutely doable. There's ample supply, and you shouldn't need to have to make a major investment in a manufacturing plant to be able to do genetic medicines.

Sure. Absolutely. So what we're providing is an update on our ongoing Phase 1/2 study. And so some of the key highlights are: first, a continued very high durability of response. So the protein that this gene therapy, PBFT02, is making is progranulin, and we are measuring progranulin levels in the cerebrospinal fluid because that is the target and that's our measure of target engagement. And what we're looking to find is high levels and lasting over time. And the data we've shared at AIC is really a continuation of what we've shown before, that through 18 months we've shown very high and very durable CSF progranulin responses. So our target engagement is high. There have been other genetic medicines in this space that have shown a decline in CSF progranulin after a single dose of an AAV, and that's what we want to show does not happen with our product. If you're getting a gene therapy, you do want the effect to be permanent. You want it to be a one-time administration. And so very good signs there for durability.

The second thing I'll say is that the product continues to show a slowing of neurodegeneration, and we measure that by looking at plasma neurofilament levels. So plasma neurofilaments are the only biomarker in FTD-GRN where we understand what the natural history looks like. And so in the natural history data — and really we replicated some natural history data with our own analysis — in both of these analyses, it's about a 29% annual increase in plasma neurofilaments in patients who are untreated. Just your normal expected FTD-GRN patients, that's the increase you would expect. And our patients so far, after a year, are at about a 4% increase. So a real separation between natural history and what we're seeing in our treated patients, which is what we want to see, that the product is slowing nerve degeneration.

And then the final new piece of data that we shared is we have started dosing patients with a lower dose because we saw such a robust progranulin response with our first dose. We made the decision to test a lower dose, and that lower dose — we only have one data point that we're sharing from it. It's very early on, but it looks very promising because it's already near the upper limits of the normal range. So if you look at what the pattern of increase in progranulin has been for our other patients, based on this early signal, we feel very good about the prospects for this lower dose.