total of 24 published senior analysts and over 650 companies covered across all sectors. If you would like more information, please visit hcwco.com. From a logistics standpoint, please make sure to reference your online conference portal that provides your individual links to your meetings and all presentations. With that being said, we wish you a productive and enjoyable day. Now, I will hand it off to William Chou, the CEO at Passage Bio.
Thanks, Vivian. Thanks for having us here. Will Chou, I'm the CEO of Passage Bio, and today I'm gonna be telling you about our lead program, so our company is a gene therapy company focused on neurodegenerative disease, and we have a lead program in the clinic called PBFT02. It is a one-time AAV therapy that raises progranulin levels. The first indication that we are in the clinic for is frontotemporal dementia patients with the granulin mutation, but because of the very strong responses that we've been seeing in this program, we are expanding to use PBFT02 in more adult neurodegenerative diseases, including FTD with the C9 mutation, ALS, and Alzheimer's disease. I'm not gonna be talking too much about our in-house manufacturing, but we do have in-house process and analytical development that allows us to de-risk our gene therapy programs for any late-stage hiccups that might happen.
We have a strong cash position with runway out to the end of the second quarter of 2026. Starting with our lead program, PBFT02 for FTD GRN. Frontotemporal dementia is the most common form of early-onset dementia. There are no approved disease-modifying therapies, and the specific population we are targeting is FTD patients who have a mutation in the granulin gene. With this mutation, they are haploinsufficient in the protein progranulin. They don't make enough progranulin, and that is the causative effect of their neurodegeneration. We are in an ongoing phase one two study of PBFT02 in these patients. PBFT02 is a one-time AAV1 gene therapy that is administered directly to the CSF, and so far, as I'm gonna share with you, we've demonstrated durable, quite differentiated elevations of CSF progranulin.
So FTD with the granulin mutation is an orphan disease, but it is certainly not an ultra-orphan disease. There are about 18,000 patients across the U.S. and Europe with FTD-GRN. In addition, as I mentioned before, we will be expanding the utilization of PBFT02 in the clinic to other larger adult neurodegenerative diseases, including FTD with the C9orf72 mutation, amyotrophic lateral sclerosis, both sporadic and familial, and Alzheimer's disease, particularly Alzheimer's patients with a single nucleotide polymorphism in the granulin gene. So let's start with a little bit of background about FTD. FTD, what I'm gonna focus on here is the clinical symptoms, because I think they are relevant when you think about the competitive set in FTD-GRN. So this is a behavioral dementia. Patients with this get a loss of inhibition, apathy, social withdrawal, a hyperorality, and some ritualistic compulsive behaviors.
The family members are doing a lot of caregiving for these patients. Usually, this is a spouse or an adult child is doing the caregiving, and with this type of a behavioral dementia, it is often hard for patients to continue to come in to the physician, so when we get to our route of administration and our one-time administration, we do think ultimately this is the perfect type of a population who could truly benefit from a one-time therapy instead of having to come back multiple times back to the physician. Now, in FTD with the Granulin mutation, there is a known cause and effect of neurodegeneration, and that is this haploinsufficiency or decrease in progranulin levels, so progranulin is critical to maintaining CNS cell homeostasis, particularly around the functioning of lysosomes.
So with levels that are too low, progranulin levels that are too low, you get lysosomal dysfunction, a pathogenic inflammatory response. TDP-43 pathology is a final common pathway, and we're gonna be talking about that a little bit later, but ultimately, that leads to neuronal dysfunction, inflammation, and ultimately neurodegeneration. Now, there is something interesting about the normal homeostasis about progranulin that makes this target so amenable to gene therapy, so progranulin is a secreted protein in its natural homeostasis, so it is secreted by a variety of cells into the extracellular fluid. Then, it is endocytosed by neurons via a variety of cell surface receptors, and then once inside the cell, progranulin exerts its positive effects on lysosomal function, and because progranulin exists extracellularly in its natural state and is endocytosed as part of the natural functioning of progranulin, we can leverage cross-correction....
which means that not every cell that you want to affect needs to be transduced. This product can transduce other cells in the CNS that will generate progranulin, and that progranulin can be endocytosed, taken in the cells, and exert a positive function. So unlike in other gene therapies, say, in muscular dystrophy, where every single cell you want to affect, you need to transduce that cell, we can benefit from cross-correction. And what we have found is that our AAV1 has a preferential transduction of a type of cell in the CNS called an ependymal cell that lives forever. Ependymal cells live forever. They line the ventricles of the brain, and these ependymal cells are what create CSF.
So the ependymal cells, as well as other cells in the CNS, serve as factories, essentially, to create progranulin and put it into the CSF to be taken up by neurons throughout the brain. Now, a bit about our ongoing phase I/II study. So the name of the study is upliFT-D. It is a multicenter, multi-nation study, so we have seven sites open across the U.S., Canada, Brazil, and Portugal. It's an open-label dose escalation study. Originally, we had planned to dose escalate up to a three X higher dose in cohort two, and we have an optional even higher dose for cohort three. Well, we've treated the first five patients so far in cohort one, and because of the very strong progranulin response that we've seen already, we have elected to keep the same dose moving forward in cohort two.
Cohort two is really just an extension of cohort one. The only difference being is that we can enroll cohort two in parallel. We don't need to wait 60 days between dosing patients, as we did for the first three patients in cohort one. The primary endpoints are safety and tolerability. Of course, the most important biomarker that we are looking at initially is progranulin levels. What is the level of target engagement that we are getting with this product? And we are looking at a variety of other exploratory biomarkers, from markers of lysosomal dysfunction, as seen at the bottom, to measures of pathogenic inflammation, such as GFAP, to measures of neurodegeneration, such as neurofilaments, and ultimately, the clinical dementia rating scale modified for FTD is a clinical outcome that we are looking at as well. Our route of administration is intra-cisterna magna.
The cisterna magna is a pocket of cerebrospinal fluid at the base of the brain that is outside the brain parenchyma, and we do a direct delivery. It is about a 45-minute procedure done by an interventional radiologist under CT guidance, so no neurosurgery is necessary, and it's a relatively brief procedure. Patient is in and out of the CT suite in under an hour. Giving this product directly to the CNS allows for a few things. First, broad CNS biodistribution. We have found in ICM administration, broad distribution of vectors throughout the brain, including the deep parts of the brain, in equal amounts as to the cortex. We can also use lower doses than IV systemic delivery because we don't have to cross the blood-brain barrier. We're giving the vector directly into the CNS, and we have a reduced impact of neutralizing antibodies.
We do have vector that spills over into the systemic, into the periphery, and therefore, we do need immunosuppression, but overall, we need a generally lower level of immunosuppression than IV-administered AAVs. Okay, so what have we found from our ongoing study? So we have shared target engagement data from the first three patients, and we've shared initial safety data from the first five patients. So the first patient who was treated with PBFT02, they were given a relatively low level of immunosuppression, just 60 milligrams of oral prednisone a day. That first patient had two SAEs that were related to an immune response, so we then modified the protocol.
We increased the steroids to three days of pulse IV steroids, followed by a sixty-day course of oral steroids, and the subsequent four patients who received that higher dose of immunosuppression have had no SAEs. There's been no evidence of LFT abnormalities, and really, it's been quite clean for all four of these patients. There's been no evidence in any patient of dorsal root ganglion toxicity, as measured by nerve conduction studies, and we've seen no complications related to our ICM procedure. Now, in terms of efficacy and target engagement, I'm gonna talk about that in the next slide. So here is a measure of the target, which is CSF levels of progranulin. Remember, progranulin is the missing protein that is haploinsufficient in these patients. And what you can hear and see on the Y-axis is CSF progranulin.
The gray shaded area is the normal range, so it's about three to eight in unaffected patients. All of our patients started below three, so they started anywhere from about 1.9 to 2.9, and you can see a very consistent increase at 30 days that continues out at 6 months. We have achieved levels of 21 to 27, and I will say that looking at other clinical data in FTD-GRN, these are the highest levels of CSF progranulin that we've seen in the clinic so far in FTD patients with the granulin mutation. So there are some other programs that are in the clinic right now that have netted out in this three to eight range on average over time. So we feel very good that this is a differentiated profile.
Now, we do get asked the question from time to time: how do you know that a higher level of progranulin actually is going to make a difference in the clinic on CDR, on rate of clinical decline? And that is a very valid question, and I would answer this in a couple ways. First, well, the only way you can find this out is actually doing the studies, because there's been no other study so far until this recent batch of of current studies in the clinic testing raising progranulin. So we don't know. However, what we do know, and what us and pretty much everyone in the field believes, is there is a threshold of CSF progranulin level that one needs to get over to actually have a clinical benefit. What is unknown is what is that level?
What is that threshold that you need to get over? What we can say is that on average, our levels - patients are gonna vary, and there's gonna be variability, but on average, our levels are going to be higher than other programs that we've seen. And therefore, we believe this product has the greatest chance of, for any given patient, getting that patient over that threshold, and therefore, having a higher response rate. One other thing to note is that because we deliver this product directly to the CSF, this product does not elevate plasma levels of progranulin. So here you see plasma progranulin. The gray area is the low range of normal for plasma progranulin, and as you can see, for our first three patients, they really haven't moved at all from a plasma progranulin standpoint.
It's important because we want to raise progranulin in the target tissue, which is in CNS, and we don't want to raise it anywhere else because we want to... We want the action to happen where we're going to correct deficit, and not where there could be any unknown side effects. Okay, so looking ahead, PBFT02 has the opportunity to really correct pathology beyond just FTD patients with a granulin mutation. And as I mentioned before, patients with FTD-GRN, they have a final common pathway of cellular pathology called TDP-43 pathology. So TDP-43 is a protein that should be in the nucleus of cells, and in this pathology, it mislocalizes to the cytoplasm, and there, causes inclusion bodies and ultimately neurodegeneration.
TDP-43 is the hallmark of not just FTD patients with a granulin mutation, but also FTD patients who have the C9orf72 mutation, as well as 95% of ALS patients have TDP-43 pathology. And what we've seen in preclinical models is that elevating progranulin has been shown in multiple preclinical models to ameliorate TDP-43 pathology. So on the left is a TDP-43 knockout mouse, and on the far left panel is human progranulin levels after giving this model, this murine model, an AAV that encodes for humanized progranulin. So I would just focus on the yellow bars. This is your knockout mouse without the AAV, and the knockout mouse with the AAV, you can see, gets the progranulin levels on average in the mid-teens.
Now, looking on the right panel here, TDP-43 pathology is the Y-axis, and again, looking at the yellow bars, the knockout mouse, untreated, has very high levels of TDP-43 pathology. And when they get the AAV that encodes for progranulin, the levels of TDP-43 pathology are markedly reduced. On the right two panels is a different, murine model, but with essentially the same results. So here, the Y-axis is relative levels of insoluble TDP-43, and the black is a non-transgenic mouse. The index level is at one. The gray bar is a TDP-43 transgenic mouse with more than two X levels of insoluble TDP-43. And the clear bar is the TDP-43 transgenic mouse that has been crossed with a mouse that overexpresses progranulin, and it expresses progranulin at levels of about more than two times endogenous levels.
In this crossed mouse, you can see the TDP-43 pathology is reduced almost to the non-transgenic mouse level. Also, in terms of survival, the crossed mice, who have high levels of progranulin, have increased overall survival versus the transgenic TDP-43 mouse. These are just a couple of examples of the preclinical evidence that higher progranulin levels can ameliorate TDP-43, which is why we're so excited to be pursuing PBFT02 in these additional indications. As far as looking forward, we've got several milestones coming up. The most proximal, in the second half of this year, in September, we will be presenting updated safety and biomarker data from cohort one at the ISFTD conference in Amsterdam in the third week of September. In the first half of next year, we will be reporting twelve-month cohort one and interim cohort two data.
And in the second half of 2025, we will go to the FDA to seek regulatory feedback on pivotal trial design. In terms of our indication expansion, we have already received positive feedback from the FDA to move forward with PBFT02 in FTD patients with the C9orf72 mutation, and we will target initiating dosing of those patients in the first half of next year. In the second half of this year, we will be going back to the FDA to talk about expanding PBFT02 into ALS patients as well. We also have a program that is still preclinical in Huntington's disease. We have successfully outlicensed our pediatric clinical-stage programs in GM1 , Krabbe, and MLD to Gemma Biotherapeutics, and we have a cash balance of $92 million as of June 30, 2024.
And as I mentioned before, runway to the end of 2Q 2026, including the proceeds from our outlicensing of the pediatric programs. So with that, I want to thank you very much for your attention, and I hope you have a great conference.
Great. Thank you, Will, and thank you to Passage Bio for leading a very productive and informative presentation. The H.C. Wainwright team is grateful for your presence at the annual Global Investment Conference and for your efforts in preparing for your session. Bye.