Everyone, and thank you for joining both live and on the webcast for this first presentation of the day as part of Canaccord Genuity's 44th Annual, don't believe the slide, 44th Annual Growth Conference here in Boston. I'm Whitney Ijem, one of the analysts on the biotech team here, and it is my pleasure to turn it over to Dr. Will Chou, President and CEO of Passage Bio. Thanks, Will.
All right. Thanks very much, Whitney. Thank you for having us here. So I'm Will Chou, CEO of Passage Bio. We are a gene therapy company focused on neurodegenerative disease. We have a lead product that is in the clinic for frontotemporal dementia with the granulin mutation. We're also exploring PBFT02, our lead product, in multiple other larger neurodegenerative diseases. I'm not gonna talk much about our manufacturing today, but we have in-house process and analytical development, such that we have significantly de-risked this program in moving towards a suspension process, as well as developing our own potency assay. And we recently successfully out-licensed our legacy pediatric portfolio, and with that, we have runway to the end of Q2 2026. So a little bit about PBFT02.
The lead indication is in frontotemporal dementia, which is the leading cause of early-onset dementia, and we are treating specifically patients with a granulin mutation. These patients have a deficiency in the protein progranulin, and that's what leads to their neurodegeneration. So this is a one-time AAV1 therapy, and based on what I'm gonna share with you, we do believe it is a fairly differentiated product profile in a relatively crowded, competitive market. So, there are a lot of market entrants because, while FTD-GRN is an orphan disease, it is not a ultra-orphan disease. There are about 18,000 patients across the U.S. and Europe with FTD-GRN. The other indications that we will be expanding PBFT02 into, are even larger. So FTD- C9 has about 21,000 patients.
So, between FTD-C9 and FTD-GRN, our current study will be treating about 20%-25% of all FTD patients. We'll also be treating ALS, so both the sporadic and familial kinds, and as well as Alzheimer's disease. So about a third of patients with Alzheimer's disease have a single nucleotide polymorphism in the granulin gene and therefore have lower levels of progranulin, so this is our initial target population for AD. A little bit more about FTD, in particular because it relates to the competitive environment. So the clinical symptoms about FTD are loss of inhibition, apathy, social withdrawal, hyperorality, and compulsive behavior, so this is a behavioral dementia. This means that the caregivers of FTD patients have a difficult job, so bringing them to get treatment is not an easy thing.
We are a one-time therapy, and when we talk about the competition, I do think you have to think about what these patients and their families go through when you think about getting care. The other big thing to know is there are currently no approved disease-modifying therapies for FTD. An important thing about the physiology of progranulin really lends itself well to gene therapy. Progranulin is a secreted protein. It is secreted from multiple cells in the CNS into the extracellular space. It is then endocytosed via multiple receptors on the neuron. It needs to get inside the neuron to have its positive effects on the lysosome. But the fact that it exists in normal homeostasis in the extracellular space means that we can take advantage of cross-correction.
Our vector does not have to get into every cell that is at risk for disease. We can transduce other cells in the CNS, they can secrete the progranulin, they can be factories for progranulin, and then it is taken up by the neurons. So we call this cross-correction, and it's very advantageous because you don't have to use as high doses of vector as if, as in, say, muscular dystrophy, where you have to transduce every single cell that you want to affect. Okay, so, a little bit about our ongoing phase I/II study. This is a multicenter. We have seven sites open now across the U.S., Canada, Brazil, and Portugal, with more sites opening later this year. It's an open-label dose escalation study. It was intended to have three cohorts that dose escalate of about five patients per cohort.
We've treated five patients so far in the first cohort at the lowest dose, and because the response was so strong, we have elected to stay at the same dose, dose one, for the second cohort, and I'll share with you some of that data in a second. The implications of this are important, particularly for the speed of recruitment, because the second cohort, we no longer have to treat a patient, wait 60 days, have an IDMC review, and then treat another patient. It made for very slow recruitment of cohort one. We have a bolus of patients who... We've already had the first patient enroll in cohort two, one week after our IDMC meeting. We have a bolus of other patients who are all ready to enter, and they're probably all gonna be treated within a couple of months of each other, which is great.
Working in parallel is much more efficient. So the key biomarkers, so obviously, safety and tolerability is important for progranulin is target engagement, so that is the number one proximal biomarker we're looking for. The next biomarker down the line would be markers of lysosomal dysfunction, so these exploratory biomarkers at the bottom, cathepsin D, LAMP1, LGL1. After that, you would look at things like GFAP, which is pathologic inflammation. It's a little further down the cascade. Neurofilaments, a sign of neurodegeneration, and then finally, clinical changes and volumetric MRI changes. Okay, how is our product administered? It's administered via the intracisternal magna route. So the cisterna magna is a pocket of CSF that is at the base of the skull, but outside the parenchyma of the brain.
So by delivering ICM, it allows for broad CNS biodistribution throughout the brain and the spinal cord, much lower doses compared to IV systemic therapy. So we're talking about two to three logs lower doses, and a reduced impact of neutralizing antibodies. So while we still need immunosuppression, it's much lower levels of immunosuppression than systemic administered AAVs. It's a 45-minute procedure. It's done by an interventional radiologist. We do not require a neurosurgeon, and there is no actual penetration of the brain parenchyma with the needle. Okay, so what did our initial data look like? So we have shared safety data from the first five patients and target engagement from the first three patients. From a safety standpoint, the first patient we treated, we used a very low dose of immunosuppression. It was only 60 mg of oral prednisone for two months.
That patient had two SAEs that were related to an immune response. We then increased the steroid regimen to give pulse IV steroids, and the subsequent four patients who've been treated with a higher immunosuppression have had no SAEs at all. No patient has had any evidence of DRG toxicity. Oops! Whoa, what happened here? And we've had no complications related to ICM. So from a safety standpoint, we have been really waiting to share the full cohort one data, and we recently shared that at earnings, at least at a high level, that there have been no SAEs in any of those four patients who got the higher immunosuppression. So it's significant for us because we really do think we've got the, we've got the immunosuppression regimen figured out.
The interim efficacy target engagement data I'm gonna share with you really looks like this program has the potential to be best in class in, in this space. So this is our CSF progranulin target engagement. So the y-axis is CSF progranulin. That shaded gray area is the normal level in, in unaffected patients, so it's about three to eight. I would also say that level represents where other programs in this space that have published any data are as well. So there's an anti-sortilin antibody program, that their phase II data showed levels of about five to six, and at levels of five to six, they had changes in all of the biomarkers that I shared with you before, as well as showing clinical changes versus a natural history. There was also another AAV program. It is an AAV9 that's also delivered ICM.
The profile of that product also at 12 months, showed levels that were in this gray range. So if you look at really where we stand, so a couple of things: one, remarkably consistent for the first three patients, so all higher than the normal levels and markedly higher than any other programs in the clinic right now. Now, I get asked a question a lot: "Why do you think that higher levels are better? Do you have any evidence that getting to higher levels actually makes a difference for patients?" And the answer is, nobody knows. Okay? Nobody, nobody knows what the threshold level of progranulin that any product needs to get over to actually have a clinical effect. But certainly, everyone in this field believes there is a threshold. You have to get above a certain level to believe you're gonna have an effect.
There is gonna be variability patient to patient. Some patients are gonna have more of a response, some are gonna have less. If we are on average, if this product is on average, able to get to a much higher level, our variability is gonna be around a much higher point, and so the odds of us having a responder are going to be higher. It's like if you're treating cholesterol, you wanna lower cholesterol as much as possible. The odds of you getting below an LDL below 200 are higher if you have a stronger product. So we, we do think that this is pretty differentiated in the market, and I know, we're gonna talk a little bit more about the competition in a second.
So because this program has had such a strong progranulin response, we have decided to move it into other indications as well. So TDP-43 is a protein that should be in the nucleus of cells, and in TDP-43 pathology, this protein mislocalizes to the cytoplasm, and there it causes inclusion bodies and neurodegeneration. This is, in fact, the final common pathway for patients with FTD, with a granulin mutation, but it's also the pathology in FTD-C9 and also in almost all patients with ALS.... And what we've seen from the preclinical evidence in multiple, preclinical studies that are not even ours, these are third-party preclinical studies, is that high levels of progranulin, getting to about two to three times the normal levels of progranulin, have been shown to ameliorate TDP-43.
So there's one murine model on the left, and just focus on the yellow bars 'cause these are the TDP-43 knockout mice. The left, the far left graph shows progranulin levels, and this is giving an AAV that increases progranulin to these mice. And you can see that the AAV mice actually have higher levels of progranulin that are importantly in about the teens, the high teen range. On the right side of that left panel is the y-axis is TDP-43 pathology, and you can see in the light yellow is the untreated knockout mouse, very high levels of TDP-43 pathology. And in the slightly darker yellow is the knockout mouse that got the AAV, that has the higher progranulin levels, markedly reduced TDP-43. On the right, similar findings, completely different mouse model, different methodology. This was not an AAV.
So, you're looking again, the y-axis is insoluble TDP-43 levels. The black bar is a non-transgenic mouse, so that's your control. That's a level of one. So this is relative levels of TDP-43. The gray bar is a different TDP-43 knockout mouse, and you can see the levels are more than two times higher than the non-transgenic mouse. And the clear bar is that TDP-43 knockout mouse crossed with a mouse that overexpresses human progranulin, and it expresses about two to three times normal, the normal level in a mouse. And you can see a dramatic reduction in the TDP-43 pathology. And on the right, there's also a difference. These cross mice had longer survival than the transgenic mice. So there's a fair amount of preclinical evidence that raising progranulin will work for TDP-43 pathology.
But in all these preclinical studies, you had to get progranulin levels pretty high. So it was about in the levels of the teens or two to three x a normal level. And so far, we're the only program that's been able to show that in humans in the clinic. Because of this, we, we went to the FDA and asked them about pursuing using PBFT02 for FTD-C9 patients, and they, they quickly approved that. And so we're moving forward with a protocol amendment to expand our current trial to treat FTD-C9 patients. So my last slide, and then I'll take questions, is upcoming milestones. So we have so far shared only progranulin data for the first three patients and only out to six months.
So there is a meeting in Amsterdam in September, so we will be sharing at the ISFTD meeting, updated data from all five patients. So we'll go through the details of their safety data, and we hope to answer some of the outstanding questions about our, our product profile. So first, can you consistently show across multiple patients these high levels, or are you gonna get a lot of variability? Some of our competitors have shown very high levels of variability, even with an AAV. And second, importantly, there's been signs in other AAV programs of decline out to 12 months. And so while we won't have lots of 12-month data, we will have some 12-month data to share at ISFTD, and it's important, for us to distinguish between other programs that have lost their efficacy over time.
In the first half of 2025, we'll report additional data from cohort one, as well as the first data from cohort two. We will seek regulatory feedback via an end-of-phase two meeting in the second half of 2025. Later on this year, we'll be going back to the FDA to expand the PBFT02 to ALS patients. And our plan is to initiate dosing of FTD-C9 patients also in the first half of next year. So I think I covered everything else. We also have a Huntington, Huntington's preclinical program that we pursue with GTP, with the gene therapy program at Penn. Since the gene therapy program at Penn has moved to Gemma Biotherapeutics, our entire preclinical program has also moved to Gemma. It is the same people, in the same space, doing the same work, just under a different name.
And with that, we've got about 10 minutes for Q&A, so I'll open up to questions.
Excellent. I'll start. We can leave it on this slide because I actually want to take the opportunity-
Mm-hmm.
to dive into ISFTD a little bit more. So you talked about more detailed safety data. Is that really the focus, or could we see some additional biomarker data you had? Kind of all, several biomarkers listed on this slide that would be important to look at. So yes, are there other biomarkers or other things we should know?
Sure. Well, we're certainly collecting all those biomarkers, but we're not planning on sharing those biomarkers at this readout. We have a very limited number of patients with long-term follow-up. So if you look, there's a lot of variability when we look at the other programs, in not just progranulin, but also these exploratory biomarkers. So when we look at what other programs have done, it's been about 10 patients followed out for a year, and then they've shared kind of en masse, what do those biomarkers look like? I'm not saying we're gonna need a full 10 patients for a year, but we're certainly gonna need more than one or two patients for a year. You have to have enough of an N to really make something out of these exploratory biomarkers.
That, that makes sense. Going back to the safety question-
Mm-hmm.
and the progranulin levels.
Yeah.
So you kind of talked about this a little bit, but can you expand a little bit more? Like, is there a level at which there's too much? So how do you think about that, and I guess maybe as part of that, can you talk a little bit about the competitive landscape in that regard?
Yeah, sure. So first, if you search through the literature, there is no literature, no evidence at all, that high levels of progranulin have any toxicity. In our NHP studies, we got up to about 70. We know that Denali in healthy volunteers has gotten higher than 70, and the only mention of deleterious effects of progranulin are in the solid tumor microenvironment. If you have a pre-existing tumor and it secretes progranulin, that could drive growth, but progranulin itself is not oncogenic at all. So, there's no known deleterious effects of high levels of progranulin. I will say one other. So we've done all our research on this, but what is very satisfying is we shared this data, this six-month data, with the FDA when we asked them to go into FTD-C9.
FTD-C9 patients start out in the normal level, so they start out at about five to six, whereas GRN patients are starting out below three. So one would expect that FTD-C9, if we give them the exact same dose, they're gonna go even higher than 27. They'll probably go 30, 33. And we explained all this to the FDA, and we advocated, we wanna start at dose one in FTD-C9 patients because there is no evidence that there's any toxicity from progranulin. And the FDA agreed with us to start at dose one in FTD-C9. So if you're worried that maybe we're not finding something and that somebody else knows something, well, in fact, just look at the FTD-C9, dose one. They said we could just start right there at that dose.
Got it. Okay, that's, that's very helpful.
Mm-hmm.
And just to go back to the pre-existing tumor comment, that's something you look [audio disctortion].
Yes. Pre-existing tumors are not really relevant because all these patients get imaging before they come into the study, and certainly anyone who's gonna get imaging in a commercial environment before they get this product, you have to get imaging to get the ICM, and you have to make sure there's no—you don't have any venous malformations 'cause we're using a needle. So nobody's gonna have CNS tumors, and from a peripheral standpoint, we don't raise peripheral levels of progranulin, so if you have an occult tumor peripherally, then it doesn't matter because we're not raising progranulin outside the CNS.
Okay, that's helpful.
Mm-hmm.
Diving into the competitive landscape-
Sure.
... a little bit more, you touched on this, but yeah, what are you seeing from an AAV perspective, as you talked about another program? What are the key points of differentiation-
Sure.
from yours, and then, and then maybe looking outside of AAV as well?
Yeah, sure. There is a AAV9 program that Lilly is conducting, and we always thought from our preclinical studies that our capsid, we use an AAV1, was going to get to higher levels of progranulin just because that's what our NHP study showed. That has in fact been true. Their levels at about 12 months are around eigh, but interestingly, they start out much higher at day 60 and then decline over time out to 12 months. So there is a question about durability. No one understands why. It's not what I would have expected at all from an AAV.
We don't know why it's happening, but they have seen a decline on average over time that is fairly significant, which is why it's so important for us to start sharing the 12-month data to see, is this a class effect or is or are there differences between capsids?
Fair enough. Okay. And in terms of the promoters or some other factors, I guess, that we should be thinking about as it relates to durability, any-
It could be. Sure, of course, it could be the construct itself. There could be something about the construct and that, the types of cells it transduces or the preferential transduction of some cells that is different, that may be deleterious to cells, that causes cells that are transduced to, instead of be immortal, to die off. So yes, there could be something to do with the actual constructs.
Okay, excellent. Excellent. And so then to your point, at ISFTD with a little bit of data at 12 months, I think you said one to two patients, how, how de-risking do you think that data will be to answer or start to answer that question?
Well, look, it's going to be a small n, and it will be, what we have-
Right.
... right now. So how de-risking will it be? I think you get early signals from, from data, right? And at a low end, you can't be sure, but certainly you'd rather have positive early signals instead of negative early signals.
Mm-hmm. Fair enough. Fair enough. Okay, and then in terms of the non-gene therapy competitive landscape as well-
Mm-hmm.
Again, you've touched on it, but can you speak a little bit more to the point of peripheral versus CNS progranulin and kind of how that's an important point of differentiation or aspect of the direct to CNS approach?
Yeah, so, the anti-sortilin antibody is delivered IV. I think that there's two big differences. Well, there's three big differences. One is that that program has finished enrolling it, the phase III study. So it's fantastic. They've generated a lot of momentum and excitement among the community. They're also generating a lot of great evidence that is really helpful that they can raise progranulin, even a modest amount, and have major effects on outcomes. So that's important. The product is administered once a month, so it's once a month, basically forever. You have to keep getting on the product. And as I mentioned before, this is a behavioral dementia. It's gonna be hard to come in once a month-...
pretty much forever, and we do think a one-time therapy is advantageous, particularly for families taking care of somebody with a behavioral dementia. There's other programs. The Denali program also has an IV systemically administered product. That we think is about once every two weeks, so that can get to even higher levels, probably as high as we can in progranulin. But again, once every couple weeks is gonna be difficult for patients.
Mm-hmm. Got it. Okay. And in the last couple-
Mm-hmm.
-minutes, what do you, I guess, need to see from, I guess, additional follow-up in cohort one and then in early cohort two data, to kind of get confident and move to the next steps? And what are the next steps?
Sure, sure. So the most important thing is for us to determine what the right dose is to bring into a pivotal study. So that's one. To do that, we need to see consistent Progranulin response, and we need to see it be durable over time, especially when other AAV programs have shown lack of durability. So if we can continue to see consistent, durable response, we can identify what the dose is. Because, yes, there are many other biomarkers that we need to look at. They're gonna take some time to read out, and based on what we've seen from the literature and from what our competitors are doing, we're pretty confident we're gonna change the biomarkers. Because even at a modest improvement in progranulin, those biomarkers have all changed. So for us, it is, can we consistently get to the right levels of progranulin?
That's why we've targeted second half of next year for an end of phase II meeting. Because at that point, we'll have at least safety data of about 10 patients. We'll have 12 months of progranulin data from several patients, and so that's gonna be enough for us to say, "Okay, this is the right dose to bring in."
Mm-hmm. Okay, got it.
Mm-hmm.
And then, in terms of next steps, meeting with the FDA, but any early thoughts on what the pivotal path looks here? Like, is there a biomarker more so registered?
Yeah, sure. So there is a base case strategy, which is the what currently Alector is doing, which is a randomized placebo-controlled study with clinical endpoints. There are also upside scenarios, so we are working with CBER, and CBER has expressed a lot of interest in, particularly for rare diseases with no treatment, having accelerated approval. There are excellent biomarkers, both biomarkers of lysosomal dysfunction, biomarkers of neurodegeneration, such as neurofilaments. These biomarkers are not as mature as in other areas. So this is not the same as, say, ALS, where there is a lot of data already on neurofilaments. So the data needs to be built. We are in the process of building that data, but we do believe that we can start making that case, and as we generate more data, there is a potential for accelerated approval.
Excellent. All right.
Yeah.
We will be staying tuned for updates in that regard. Unless there's any more questions in the room, thank you very much for taking the time.
Okay. Thanks for having us.