Okay, good afternoon, everyone. I'm William Chou. I'm the CEO of Passage Bio. I'll take you through our plans coming up. So, we are a gene therapy company focused on neurodegenerative disease, and I'm going to spend most of the time today talking about our PBFT02. It is an AAV1 of protein progranulin. The first indication we're going after is FTD with a GRN mutation, but because progranulin has an effect on multiple neurodegenerative diseases, we're actually going to be pursuing it in other indications as well. So a little bit about frontotemporal dementia. So FTD-GRN is the one genetic form of FTD. It leads to a deficiency in a protein called progranulin.
and what I'm going to share with you today is from our initial data from our Phase I/II study, it looks like we really have a very differentiated product, and that this product can raise progranulin levels in a way that no other clinical program can. And it can do it in a durable fashion. So looking forward to sharing with you that data. So a little bit on epidemiology here. So FTD with the GRN mutation is about 18,000 patients across the U.S. and Europe, so it's a rare disease, but it is certainly not ultra-rare.
And because of the really fantastic results we've seen so far with the first indication, we're going to be pursuing larger neurodegenerative diseases, and I'm going to share with you why we think that elevated progranulin can affect FTD-C9, sporadic ALS, which is 95% of ALS patients, as well as Alzheimer's disease and a subset of Alzheimer's patients, those who have a single nucleotide polymorphism in the granulin gene. Okay, so a little bit about PBFT02 and our lead indication. So what is FTD? So it's a fatal onset neurodegenerative disease. It is the most common cause of early dementia, so onset on average in the 50s, results in loss of inhibition, apathy, social withdrawal, hyperorality, ritualistic compulsive behaviors. Patients unfortunately die after about 8 years. And importantly, there are absolutely no disease-modifying therapies currently approved for FTD, for any type of FTD, genetic or sporadic.
Huge unmet need. This is a disease that both Wendy Williams and Bruce Willis, unfortunately. Okay. Now, in FTD with the GRN mutation, the proximal cause of neurodegeneration for these patients is low levels of progranulin. You get low levels of progranulin, that leads to neuronal dysfunction via really pathogenic inflammation that and also TDP-43 pathology. I'm going to talk more about TDP-43 pathology because it is an important intersection of multiple neurodegenerative diseases. The thing about using an AAV that raises progranulin that is different from other Gene Therapy Program is you don't have to transduce every affected cell or every at-risk cell. So you can transduce other cells in the CNS, they can create progranulin, it can go to the extracellular fluid, and the natural homeostasis, the cycle, the pathway of progranulin, is that it is manufactured in neurons and microglia.
It is secreted into the extracellular fluid, and then it is endocytosed via a variety of receptors by neurons, and it exerts its effect inside the cell. It has a positive effect on lysosomal function inside the cell. You have to get it inside the cells for it to work. We can leverage this natural pathway by transducing any cell in the CNS and using that cell as a factory for creating progranulin. The interesting thing about our product is the AAV1 cap, AAV1 capsid that we use has a particular tropism for cells called ependymal cells, and they line the ventricles, and the ventricles are what holds all the CSF.
So especially compared versus AAV9, AAV1s transduce these ependymal cells much better, and they essentially dump large amounts of progranulin directly into the CSF, and that is our hypothesis for why our AAV1 dramatically outperforms an AAV9. And the important thing here is that ependymal cells are everlasting, like neurons. They don't turn over, and we believe that's why we're seeing such good durability with this product. Okay, a little bit about our ongoing phase I/II trials. So we have 7 sites right now across 4 countries: U.S., Canada, Brazil, and Portugal. It is a dose escalation study with 2 mandatory cohorts and 1 optional third cohort.
We have already treated all five patients in the first cohort, and based on the really stellar results we're seeing in terms of target engagement and CSF progranulin levels, we have made the decision that we don't need to go up in dose. We're absolutely fine at the current dose, and so cohort two is going to be the same dose as cohort one. Primary endpoints are safety and tolerability. The key biomarker we're looking at right now is target engagement, so that's CSF progranulin is the key biomarker, but we're also looking at a host of other biomarkers. So exploratory ones, which mostly are looking at measures of lysosomal dysfunction, and also other biomarkers which measure pathogenic inflammation, down to neurofilaments, down to clinical response and measured by the CDR. Okay, so how are we administering this product?
So we're administering it directly to the CSF via intracisterna magna route. So this procedure is about a 45-minute procedure. So the cisterna magna is a large reservoir of CSF that is at the base of the skull and that is outside the brain parenchyma. So it's about a 45-minute procedure. It's done under CT guidance. It requires only an interventional radiologist, so no neurosurgeon needed, 45 minutes about, and no penetration of the brain parenchyma. So the needle is not going all the way through brain parenchyma. We're not causing any micro lesions in the brain. Yeah. Yeah, yeah, sure. It's not through a catheter. It's a small gauge. So we had a question in the audience, was it just through the needle? And there's no catheter at all. It's very close. So cisterna magna is not that far from the skin.
So why do we deliver directly to the CNS? First, it allows for a broad CNS distribution. So we have good non-human primate data that we see broad uptake of the vector throughout the brain and the spinal cord. We use much lower doses compared to IV systemic therapy. So the dose level that we're giving right now, if you convert it to the genome copies per kilogram, metric, it is about in the mid-10^11 genome copies per kilogram. So that's two to three logs lower than what you're giving, systemically. So markedly lower, and we don't have to worry about neutralizing anybody because they're in the periphery, and we don't even test for neutralizing anybody as screening criteria. Okay, so I'm going to talk about safety first, what we've seen, then I'll go through the efficacy.
From a safety standpoint, when we started the protocol, because of the relatively immunoprotected space in the CSF, we started with a very low level of immunosuppression, so it's just 60 mg of oral prednisone daily for 2 months, and that wasn't quite enough. So that first patient had 2 SAEs that were essentially an immune response. They responded to IV steroids. And so after that first patient, we raised the steroid level, so now we give 3 days of pulse IV steroids, followed by 57 days of oral prednisone. And subsequently, patients 2 and 3 had no SAEs, no evidence of an immune response, and we've also treated patients 4 and 5. We'll be reporting on their safety this fall in September.
So from what we've seen so far, it seems like the higher immunosuppression seems to have addressed everything we saw on the first page. And the efficacy data is really what we're quite excited about. So let me spend some time on this slide here. So this is target engagement. This is the missing enzyme, progranulin, in the CSF. That is what you're seeing on the Y-axis here. The gray range of 3-8 is the normal range in unaffected adults. The average is just below 5, and the range is 3-8. The other thing I will say about that gray range of 3-8 is there's a few other programs that are in the clinic for FTD-GRN using different mechanisms, and that gray range is about what they're seeing. Okay? They're getting about to the normal level.
Our patients all started at below normal, so between 1 and 3. By day 30, they were at 11 to 17. Our two patients who we followed up to 6 months are at 22- 27. So this is markedly higher than any other program that we have seen, that we've seen data for. We don't expect it to keep going up at 6 months. I expect it to plateau, and we're looking forward to sharing even more 12-month data, at a future point. A couple questions that I generally get when we show this data is, okay, so this is fantastic. It's definitely differentiated, but how do you know this is going to make a difference for patients, a clinical difference? Because that's ultimately what we care about the most. And there's a couple of ways to answer this.
First, there's definitely preclinical data that shows if you get incrementally higher levels of progranulin, you can see an incremental effect on lysosomal function. There's some TDP-43 data that I'm going to share with you later, that is only true at levels that are 2x-3x higher than normal. But the easiest way to think about this is just from a drug development standpoint. We, who are in this field, all know, all believe that there is some threshold you have to get over of progranulin to have a clinical effect. Nobody knows what that threshold actually is. We also know for certain that no matter what product you give, there's going to be variability in your target engagement. Every modality, there's just variability patient to patient.
The fact that on average, we are so much higher than any other product, it just means we have a higher probability of getting responders. So, we look at having a better overall percent responders ultimately on a clinical outcome. Now, what you're looking at here is plasma progranulin levels, and the gray at the top is the low level of normal, and all of these patients, because they're haploinsufficient, they start at low levels of plasma progranulin, and the key thing here is they stay low. So this product does not have an effect out in the periphery. The product is directed to where the progranulin is needed. That is in the CSF. So in summary, from a safety standpoint, all the patients who've been treated with the revised immunosuppression have had a very, very favorable tox profile.
Our progranulin levels really are best in class from what we've seen, and they are durable. And so far, at least out to six months in the early first two patients, they are quite consistent. It's kind of rare to see patients look that similar. So we're excited about what we've seen so far, and I'll go through the next steps when I talk about milestones and guidance at the end. But before I do that, let me address what else we're doing with PBFT02, 'cause it hasn't really been done before in gene therapy. So, these patients with FTD with a granulin mutation, they have a pathology called TDP-43 pathology, and TDP-43 is a nuclear protein that sometimes mislocalizes into the cytoplasm, and when it mislocalizes into the cytoplasm, it causes inclusion bodies that lead to neurodegeneration and cell death.
TDP-43 pathology is a hallmark of FTD-GRN. It's also the hallmark of FTD with the C9 mutation, and also the hallmark of sporadic ALS, which is 95% of ALS patients. There is a fair amount of third-party preclinical data, it's not our, not our data, that shows if you elevate progranulin, you can ameliorate TDP-43 pathology. I'm gonna walk through a couple of examples for you here. First, on the left side of the slide, this is a TDP-43 knockout mouse, and I'll just direct you to the yellow. In this experiment, this TDP-43 knockout mouse was given an AAV that generates human progranulin. It was not us. It was done by an academic and published recently this year.
So the y-axis on the left is levels of human progranulin, and in the yellow, you can see this knockout mouse given the AAV, got to levels about in the high teens on average of human progranulin. And then the next panel over shows levels of insoluble TDP-43. And again, if you look at the knockout mouse, untreated, very high levels of TDP-43. And then if you look at that same knockout mouse with the AAV encoding for progranulin, markedly lower levels of TDP-43. Now, on the right side, basically is a different model, different type of experiment, but same result. So again, the y-axis on the third panel is relative insoluble TDP-43. The black bar is a non-transgenic mouse, so it's the index level of one. The gray bar is a TDP-43 transgenic mouse, so it has more than twice the level of insoluble TDP-43.
Then that clear bar is that TDP-43 transgenic mouse that is crossed with a mouse that overexpresses human progranulin, and the levels of progranulin it got to were about 2x-3x the normal level. And you can see the TDP-43, the insoluble TDP-43 level, went way down, almost down to the index level. And on the right is a survival curve, and the top darker curve is the survival of the crossed mice that had the higher progranulin levels and lower TDP-43, and their survival is also improved. Both of these experiments got the progranulin levels about 2x-3x what the index mouse had. So this is some other evidence that you need to get progranulin relatively high to see a reversal of some of the cellular defects.
So this is exciting because we believe progranulin can be neuroprotective in FTD-C9orf72 as well, and in ALS, and we've given guidance that in the second half of this year, we will have gone to the FDA and talked about the fastest path forward to the clinic in these two indications. The other interesting data is in Alzheimer's disease. So, there is a particular single nucleotide polymorphism in the progranulin gene, where the carriers of this SNP have reduced progranulin levels and increased risk of Alzheimer's disease. Alzheimer's patients who have this particular SNP have reduced progranulin levels and also increased levels of tau. It is relatively common. It's about 30% of AD patients have this SNP, and it is easily diagnosed in an off-the-shelf blood test.
There's preclinical evidence that lowering progranulin levels can exacerbate pathology in AD mice, and overexpressing progranulin can reduce pathology in AD mice. So there's a lot of different lines of evidence that support elevated progranulin in Alzheimer's. We're gonna be pursuing some more preclinical research of our own to validate that ourselves, and we're looking forward to moving that project along. I think the interesting thing about all these programs is if you think about gene therapies, they are usually one product for one specific mutation, and that's the only thing that you can address with this gene therapy. Here, we have invested a lot of capital in the manufacturing and preclinical research on PBFT02, and now we are looking forward to amortizing that investment over multiple significant neurodegenerative disease indications. That generally hasn't been done before with gene therapies.
So in that way, it's a little bit more like an oncology product, in that you have an attractive target, and we have some good hypotheses that hitting that target can work in multiple indications. One thing about manufacturing, so there are obviously Gene Therapy Program s in the past have run into some trouble at the very end, or usually around a couple things, around functional potency assay and also around comparability when you're moving to a commercial manufacturing process. Because we have in-house analytical and process development, we have made the requisite investments early in both of those areas to de-risk the program, and we're really encouraged by what we're seeing so far on both of those tracks. Yeah, please, another question. Sure. Yeah. So this is AAV. Yeah. Yep. Okay, so my last slide is really on guidance.
So, we are shortly going to be initiating dosing of cohort two patients. And then in the second half of this year, we will share six months safety and biomarker data from cohort one patients. In the first half of 2025, we will share 12-month follow-up data from cohort one patients, as well as preliminary data from cohort two patients. And also in the second half of this year, we will obtain regulatory feedback on the fastest route possible to the clinic for FTD-C9 and ALS. We do also have pediatric programs that we are in the process of out-licensing, and we have an ongoing preclinical program in Huntington's disease that's also an AAV approach.
The preclinical work is being done by our partners at the University of Pennsylvania in the Gene Therapy Program , and we are really seeing great data coming out of that program. We have $105 million in cash on hand and runway out to the end of 2025, which is more than enough time to allow our data to mature in FTD-GRN. So, with that, yeah. End of 2025.
Okay, so, the stock is where it is.
Sure.
But can you maybe just discuss a little bit, the events that caused that and what changes you. If you made some changes, how, what changes you've made in light of the data feed that led to, what happened with the stock over the last.
Yeah.
While.
Yeah, so if you look at the stock over the last several years, obviously, it had quite a decline. I would say there was a couple of things that happened. Obviously, it was the entire market, so it was a difficult time for the entire market. It was particularly difficult for gene therapies. Originally, Passage Bio had multiple programs and was pursuing multiple programs at once. And given the pace of data accumulation and given the market environment, company could not afford to pursue all those programs. So, as of the end of last year, we made the difficult decision to stop all the pediatric programs and to really focus on the most promising program, which is PBFT02.
So I joined in October of 2022, and honestly, one of the things that was the most attractive for me about Passage Bio was looking at the preclinical data around PBFT02 and how it compared to other preclinical data, and even clinical data in this competitive market. And I also thought that this asset was probably being underutilized for its potential. And so we made the decision to focus on this and take that investment that we would otherwise put in the pediatric programs and put it into expanding into other adult neurodegenerative disease. And I will say since we first released some data in FTD-GRN at the end of the year, we did stop the decline, and so our goal now is just to continue generating data. You did mention the share price is where it is.
What are people missing? Well, I think people are waiting to see more from this study and to see more durable data. But the way we look at it, I like competitively where we stand in this market, and I really. If you look at other competitors in the FTD-GRN space, they're essentially all either partnered or have been acquired. So there is a lot of belief that progranulin will fix the deficit in FTD-GRN.
One of the interesting developments has been the start of the START program.
Mm-hmm.
Certain companies have been made available to that program. Were you a candidate for the program?
We were not a candidate for the program because if you look at the original RFP from the FDA, I'll call it, it was for pediatric programs. So they were focusing on onset 10 or younger. I mean, we definitely would have done it. We would have done it for our pediatric programs if we were going forward with them. My hope is that it will be a success, and they will expand this beyond pediatric programs where there's huge amounts of unmet need.
These programs that you had to furlough,
Mm-hmm.
They're just sitting on the back, and
Yep.
If you're successful, this is something that you can go back to in time? If, if you position yourself, the balance sheet allows it, these are, these are, molecules that you, haven't given up on. They're just simply postponed and you can, something you can develop later on?
Theoretically, we could. Strategically, we've made the commitment that we're going forward with adult neurodegenerative disease. We still see a lot of potential in these assets, but we also see a lot of potential in PBFT02 across and in the, eventually in the Huntington's program.
So specifically on the earlier slide.
Mm-hmm
Indicated that there's potential to expand to different treatments, so Alzheimer's one. If you were just to think about this and look at what your molecule can do.
Mm-hmm
And look at the various other treatments that are being attempted. Alzheimer's is proving to be quite elusive to get something that one can either push it out, but certainly the absolute cure is still not there. From the science perspective, can you just describe why your molecule or your—I shouldn't call it molecule, but why your gene therapy potentially could be a solution where others is not?
Yeah, so I would look at it from—for Alzheimer's, I would look at it this way, is, again, I'll go back to the oncology analogy. It's great in oncology if we have a single bullet that does everything, but usually that's not the case. Usually, you're trying everything you can because we don't have a single silver bullet, and I would look at Alzheimer's.